Parkinson's Disease, Secondary Parkinsonism, and Other Disorders Presenting with Parkinsonian Syndrome: Clinical Guidelines

List of Abbreviations

DA - dopamine agonists

PD – Parkinson's disease

SNHS - substantia nigra hyperechogenicity

DLB – dementia with Lewy bodies

EDS – excessive daytime sleepiness

MAO-B inhibitors - Monoamine oxidase (type B) inhibitors

COMT inhibitors (catechol-O-methyltransferase inhibitors) — (ATC: other dopaminergic agents)

ChEI - anticholinesterase agents

CI - cognitive impairment

CBD – corticobasal degeneration

CT – computed tomography

CBT - cognitive behavioral therapy

MSA – multiple system atrophy

MRI – magnetic resonance imaging

ICF – International Classification of Functioning, Disability and Health

SA - sleep attacks

ICD - impulse control disorder

SPECT - single-photon emission computed tomography

PSP – progressive supranuclear palsy

bvFTD – behavioral variant frontotemporal dementia

PPA – primary progressive aphasia

PET – positron emission tomography

rTMS - repetitive transcranial magnetic stimulation

RBD – rapid eye movement sleep behavior disorder

VP - vascular parkinsonism

DDS - dopamine dysregulation syndrome

RLS - restless legs syndrome

SSRI - selective serotonin reuptake inhibitors

SNRI - serotonin-norepinephrine reuptake inhibitors (ATC: other antidepressants)

TCA – tricyclic antidepressants

CVD - cerebrovascular disease

TBI – traumatic brain injury

MCI – mild cognitive impairment

DBS - deep brain stimulation

GDNF – glial cell line-derived neurotrophic factor

GPi - globus pallidus pars interna

MDS - International Parkinson and Movement Disorder Society

MDS UPDRS – Movement Disorder Society-Unified Parkinson's Disease Rating Scale

VIM – ventral intermediate nucleus

STN – subthalamic nucleus

Terms and Definitions

Hypokinesia – an obligate sign of parkinsonism, which includes 3 main components:

bradykinesia – slowness of movement, fatiguability of repetitive movements;

oligokinesia – impoverishment of movement patterns (absence of associated arm movements during walking - acheiromegaly/acheirokinesia, hypomimia, microbasia, hypophonia),

akinesia - difficulty initiating movements, freezing.

Rest tremor – rhythmic tremor with a frequency of 3 - 6 Hz, involving the distal parts, decreasing or disappearing with movement.

Muscle rigidity – increased plastic-type muscle tone, defined as resistance during passive movements.

Postural instability – inability to maintain balance when changing posture.

Gait disorders – slow, shuffling gait with shortened stride length, presence of freezing and propulsion.

Freezing of gait – difficulty initiating movements, getting "stuck" while walking.

«Wearing-off» phenomenon of dopa preparations and their derivatives – a significant increase in the severity of motor symptoms towards the end of the action of the regular dose of dopa preparations and their derivatives.

«On-off» phenomenon – abrupt alternations between states of mobility (action of dopa preparations and their derivatives) and immobility (lack of action of dopa preparations and their derivatives).

Phenomenon of unpredictable single-dose effect fluctuations of dopa preparations and their derivatives – development of "off" periods without an obvious connection to the time of administration of dopa preparations and their derivatives.

Delayed-on or no-on phenomenon of a single dose of dopaminergic drugs and their derivatives – delayed onset of action (> 60 minutes) of a dopaminergic drug and its derivatives.

Peak-dose dyskinesia – rapid choreiform or dystonic movements, usually more pronounced in the upper body, occurring during the period of maximum therapeutic effect of a single dose of a dopaminergic drug and its derivatives.

Diphasic dyskinesia - dyskinesias occurring at the beginning and end of the duration of action of each dose of a dopaminergic drug and its derivatives, disappearing during its peak effect.

Off-period dystonia - dystonia occurring during the "off" period with the development of fixed, painful abnormal postures, most commonly observed in the feet, and which may be segmental or generalized in nature.

Transfer - moving from one surface to another or from one starting position to another (rolling in bed, sitting up from a lying position, standing up, moving to another chair, etc.).

Deep brain stimulation (deep brain stimulation) is a neurosurgical treatment for Parkinson's disease involving the application of pulsed electrical current via a self-contained, fully implantable system consisting of electrodes connected to a pulse generator.

Thalamotomy – a destructive neurosurgical procedure for Parkinson's disease involving the ablation of specific thalamic nuclei.

Pallidotomy - a destructive neurosurgical procedure for Parkinson's disease involving the ablation of the internal segment of the globus pallidus.

Radiosurgery - a method of non-invasive destructive intervention on subcortical brain structures using a Gamma Knife.

Focused ultrasound — a modern minimally invasive medical technology used for ultrasonic thermal ablation of specific brain structures.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Parkinsonism - a syndrome characterized by a combination of hypokinesia with muscle rigidity, resting tremor, and postural instability, typically associated with damage to the basal ganglia and their connections.

The primary cause of parkinsonism is Parkinson's disease.

Parkinson's disease (PD) - a multisystem neurodegenerative disorder characterized by motor and non-motor symptoms leading to social, domestic, and occupational disability, reduced daily activity, and impaired quality of life.

Secondary parkinsonism is a complication of another disorder of known etiology (cerebrovascular injury, trauma, tumor, hydrocephalus, drug therapy, and toxic factors).

Parkinsonism in other multisystem neurodegenerative diseases develops due to multifocal CNS involvement affecting both the extrapyramidal and other brain systems.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

1.2.1. Etiology and pathogenesis of Parkinson's disease

The evolution of concepts regarding the causes of PD reflects the level of development of neurology and biomedical sciences as a whole, progressing along a complex path from views on an exclusively exogenous nature of the disease to the recognition (and at times absolutization) of the role of genetic factors in its etiology. To date, the significance of both exogenous and endogenous mechanisms in the development of PD has been firmly established, with the relative contribution of these factors varying across different age groups [1].

According to current concepts, approximately 5–7% of PD cases are inherited (monogenic) forms, whereas the majority of cases are sporadic and have a multifactorial origin. Sporadic PD may be based on the interaction of genetic factors and exogenous exposures, which together determine the nature of cellular detoxification and repair processes, xenobiotic turnover, as well as energy and neurotransmitter metabolism in a given individual [2].

Pathomorphologically, Parkinson's disease is characterized by a reduction in the number of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum. This, in turn, causes dysfunction of neurons in other basal ganglia, primarily disinhibition and hyperactivity of neurons in the internal segment of the globus pallidus and the substantia nigra pars reticulata. This leads to inhibition of thalamocortical neurons and impaired activation of neurons in the supplementary motor area, which is associated with the development of the core manifestations of PD [1]. Clinical and pathomorphological correlations show that initial symptoms appear when the neuronal population in the substantia nigra pars compacta is reduced by more than 50%, and striatal dopamine content drops by more than 80% [4].

In addition to dopaminergic neurons of the substantia nigra, other neuronal groups undergo degeneration in PD, including neurons of the dorsal motor nucleus of the vagus nerve, olfactory bulb neurons, noradrenergic neurons of the locus coeruleus, serotonergic neurons of the raphe nuclei, cholinergic neurons of the nucleus basalis of Meynert, as well as cerebral cortex neurons and certain autonomic plexuses. Consequently, in addition to dopamine deficiency, dysfunction of serotonergic, noradrenergic, and cholinergic systems occurs. Involvement of extranigral structures accounts for such clinical manifestations as anosmia, autonomic failure, depression, and dementia [1]. Thus, PD can be viewed, to a certain extent, as a multisystem degeneration.

1.2.2. Etiology and pathogenesis of secondary parkinsonism

The most frequent type of secondary parkinsonism is drug-induced parkinsonism. The pathogenetic effect of antipsychotics is associated with impaired dopaminergic neurotransmission due to blockade of postsynaptic receptors, as well as direct neurotoxicity. The risk of neuroleptic parkinsonism increases with higher doses of the antipsychotic (exceeding 3 months of use), as well as with the drug's binding specificity for D2 dopamine receptors combined with weak anticholinergic activity and low affinity for serotonin receptors, which is characteristic of typical antipsychotics such as haloperidol**, trifluoperazine, and perphenazine**. Treatment with medications from the diazepines, oxazepines, thiazepines, and oxepines group (clozapine, quetiapine**, olanzapine**), and other antipsychotics such as aripiprazole, carries a lower risk of parkinsonian symptoms. It is more frequently observed in females, elderly individuals, those with a history of organic brain pathology or traumatic brain injury, and individuals with a genetic predisposition to extrapyramidal disorders. The development of parkinsonism is also reported during treatment with metoclopramide**, tetrabenazine**, flunarizine, cinnarizine, selective serotonin reuptake inhibitor (SSRI) antidepressants, fatty acid derivatives, carbamazepine**, phenytoin**, and cyclosporine** [5].

Vascular parkinsonism (VP) is associated with diffuse white matter lesions in the deep regions of the cerebral hemispheres or bilateral multilunar lesions of the basal ganglia (as a complication of cerebral microangiopathy in patients with arterial hypertension, amyloid angiopathy, vasculitis, senile atherosclerosis, etc.). Sometimes the onset of VP is preceded by one or more strokes, with extrapyramidal symptoms developing in the acute period or in a delayed manner ‒ several months after the stroke, occasionally against the background of resolving pyramidal or cerebellar deficits that may have "masked" the symptoms of parkinsonism. The onset of VP can be acute, but is more commonly subacute or chronic [5, 6].

Toxic parkinsonism may be caused by manganese poisoning, in particular the use of manganese-containing narcotics based on ephedrine-like substances, as well as cyanides, pesticides, and organofluorine compounds [7].

1.2.3. Etiology and pathogenesis of parkinsonism in multisystem neurodegenerative diseases

Common multisystem neurodegenerative diseases ("parkinsonism-plus syndromes", atypical parkinsonism) include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD).

Multiple system atrophy (MSA) is a relentlessly progressive neurodegenerative disease leading to patient death on average 9 years after the onset of the first clinical manifestations. The degenerative process predominantly involves the basal ganglia, inferior olives, pons, cerebellum, lateral horns of the spinal cord, and Onuf's nucleus in the sacral spinal cord, clinically manifested by various combinations of parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal syndrome. Despite numerous studies, our understanding of the processes underlying the pathogenesis of MSA remains incomplete to this day. Data have been obtained indicating a specific role of the accumulation of toxic forms of α-synuclein (synucleinopathies) in cells, which triggers a whole cascade of pathological reactions. Mitochondrial dysfunction, impaired autophagy, and reduced trophic support of axons due to decreased expression of GDNF (glial cell line-derived neurotrophic factor) appear to play a particular role in MSA. Damage to oligodendroglia leads to secondary neuronal degeneration and, consequently, to the initiation of neuroinflammation, including microglial activation and cytokine release. Toxic α-synuclein can subsequently spread in a prion-like manner to other functionally connected brain regions, leading to multisystem damage. Multiple system atrophy has traditionally been considered a sporadic form of neurodegeneration, though the literature contains only isolated descriptions of familial cases with both autosomal dominant and autosomal recessive inheritance [8].

Progressive supranuclear palsy (PSP) is among a group of neurodegenerative diseases whose common feature is the accumulation in brain cells of pathological phosphorylated tau protein, forming neurofibrillary tangles and neuropil threads. PSP is based on the selective loss of specific groups of neurons and glial cells in various brain regions, primarily in the brainstem and basal ganglia. Familial cases are extremely rare [9].

Dementia with Lewy bodies (DLB) can be classified among synucleinopathies, a group that also includes PD and multiple system atrophy. Macroscopically, most patients with DLB, as in many other neurodegenerative diseases, show diffuse brain atrophy with widened cortical sulci and lateral ventricles, although on average it is less pronounced than in AD. Neuroimaging data also point to this, although extreme variability in the degree of cerebral atrophy should be noted for both DLB and AD. The development of dementia in DLB is associated with a degenerative process in the neocortex and limbic cortex, primarily in the anterior cingulate and parahippocampal gyri, as well as the frontal and parietal cortex. As modern functional neuroimaging methods demonstrate, a reduction in function (hypometabolism/hypoperfusion) of the occipital cortex occurs at an early stage, which can serve as one of the differential diagnostic features distinguishing DLB from AD. Thus, dysfunction of the occipital cortex, which may be associated with the early development of visuospatial impairments, appears to be related to disrupted neurochemical processes (e.g., cholinergic denervation). The development of parkinsonism observed in most DLB patients is associated with the involvement of the substantia nigra and striatum in the degenerative process, while sleep disorders stem from brainstem involvement. The development of autonomic dysfunction is explained both by brainstem nuclei damage and the involvement of peripheral autonomic structures, leading to cardiac autonomic denervation even at an early stage of the disease. Most DLB cases are sporadic; however, it appears that familial cases in DLB occur more frequently than in AD or vascular dementia [10].

Corticobasal degeneration (CBD) is a sporadic degenerative disease of the central nervous system involving predominantly the frontoparietal cortex and substantia nigra, and less frequently the striatum, ventrolateral thalamus, midbrain nuclei, cerebellar dentate nuclei, and inferior olives [11].

1.3 Epidemiology of the Disease or Condition

1.3.1. Epidemiology of Parkinson's disease

According to population-based studies, the prevalence of PD ranges from 120 to 180 per 100,000 population, and the incidence ranges from 12 to 20 per 100,000 population [12]. PD is rare before the age of 50, but prevalence and incidence rates steadily increase with age, reaching 55 per 100,000 per year in individuals over 70 [13, 14], and 220 to 304 per 100,000 per year in those over 85 [15, 16]. The prevalence of PD among individuals over 65 reaches 1–2% [17, 18]. A small population-based study conducted in the Solnechnogorsk district of the Moscow Region showed that the estimated prevalence of PD was 139.9 cases per 100,000 population, and the incidence was 16.3 cases per 100,000 population per year [19, 20, 21, 22].

PD is slightly more common in men. The male-to-female incidence ratio ranges from 1.1 to 1.8, averaging 1.2–1.3. After age 70, differences in incidence between men and women increase [23]. Most epidemiological studies demonstrate the relative stability of PD incidence and a trend toward increasing PD prevalence associated with population aging and improved survival of PD patients. It is hypothesized that in developed countries this trend may lead to a 2- to 3-fold increase in the number of PD patients in the coming decades [24].

1.3.2. Epidemiology of secondary parkinsonism

Most frequently, drug-induced parkinsonism is associated with the use of antipsychotic medications and develops in 15–60% of patients taking these drugs [25]. The incidence of neuroleptic-induced parkinsonism is 2.1–4.3 per 100,000 population [26].

Vascular parkinsonism (VP) is a relatively rare variant of parkinsonism, accounting for no more than 3–6% of parkinsonism cases. The combination of various signs of vascular disease and brain degeneration is observed 4 times more often than true VP. Parkinsonism syndrome is detected in 11% of patients with ischemic strokes and 14% of patients with the 'subcortical' form of discirculatory encephalopathy, which may indicate a broader prevalence of VP, especially mild forms, than previously assumed in recent years [27, 28]. Moreover, isolated parkinsonian symptoms that do not meet standard criteria for diagnosing parkinsonism syndrome are detected in 36% of ischemic stroke patients, including bradykinesia in 45% of patients with lacunar infarctions and 7% of patients with territorial infarctions [6].

1.3.3. Epidemiology of parkinsonism in multisystem neurodegenerative diseases

Parkinsonism in other multisystem neurodegenerative diseases accounts for no more than 10% of all parkinsonism cases. The prevalence of progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD) does not exceed 10 cases per 100,000 population, and the incidence is about 1 per 100,000 population per year [29]. CBD is less common than DLB, PSP, and MSA, with a prevalence not exceeding 5 per 100,000 [30]. The age of onset for MSA ranges from 50 to 60 years, for CBD 55 to 65, the mean age of onset for PSP is 62.9 years (range 44–75 years), and for DLB 70 years (65–75 years). Gender differences in atypical parkinsonism are minor, although CBD shows a slight female predominance, whereas DLB is more common in men (ratio 1.5:1) [31].

1.4 Features of Coding the Disease or Condition

Coding is performed according to Class VI 'Diseases of the nervous system' (G)

G20 Parkinson's disease

G21.1 Other drug-induced secondary parkinsonism

G21.2 Secondary parkinsonism due to other external agents

G21.4 Vascular parkinsonism

G23.1 Progressive supranuclear ophthalmoplegia (Steele-Richardson-Olszewski)

G23.2 Multiple system atrophy, parkinsonian type

G23.3 Multiple system atrophy, cerebellar type

G23.8 Other specified degenerative diseases of basal ganglia

1.5 Classification of the disease or condition

Based on the etiological criterion, parkinsonism [19] can be subdivided into:

Primary parkinsonism

Parkinson's disease (80%)

Juvenile parkinsonism

Secondary (symptomatic) parkinsonism

Vascular parkinsonism

Drug-induced parkinsonism

Toxic encephalopathies

Postencephalitic parkinsonism

Hydrocephalus

Tumors

Posttraumatic parkinsonism

Metabolic encephalopathies (hepatic failure, hypothyroidism)

Parkinsonism in other degenerative and hereditary CNS diseases

Sporadic diseases

Multiple system atrophy

Progressive supranuclear palsy (Steele-Richardson-Olszewski disease)

Dementia with Lewy bodies

Corticobasal degeneration

Alzheimer's disease

Creutzfeldt-Jakob disease

Hereditary diseases

Huntington's disease

Spinocerebellar degenerations

Hallervorden-Spatz disease

Frontotemporal dementia

Parkinsonism-ALS-dementia

Pallidal degenerations

Familial basal ganglia calcification

Neuroacanthocytosis

Hepatolenticular degeneration

1.6 Clinical presentation of the disease or condition

1.6.1. Clinical presentation of Parkinson's disease

In most patients, the disease manifests between the ages of 50 and 70 years. Cases with an onset before 40 years are classified as early-onset, and before 20 years as juvenile forms. According to current concepts, PD is believed to be characterized by a prolonged prodromal period. During this period, the patient may develop various non-specific non-motor symptoms: anosmia, constipation, depression, rapid eye movement sleep behavior disorder, chronic fatigue, restless legs syndrome. The first signs of PD can be detected 5–10 years before diagnosis using modern functional neuroimaging methods.

The core of the clinical picture consists of a symptom triad: hypokinesia, tremor, and muscle rigidity. The disease may begin with one of these symptoms, with others joining subsequently. Motor symptoms develop first on one side of the body and then on the opposite side. The hemiparkinsonism stage is a characteristic feature of PD, in contrast to vascular parkinsonism and variants of atypical parkinsonism. The fourth most important sign of the disease—postural instability—usually appears at a later stage [32].

Hypokinesia manifests as slowness of movement (bradykinesia), difficulty initiating movement, and a rapid decrease in amplitude and speed during repetitive movements. Manifestations of hypokinesia include: impaired fine motor skills (difficulty writing, brushing teeth, buttoning clothes, micrographia), infrequent blinking, hypomimia, pooling of saliva in the oral cavity and sialorrhea (due to swallowing disorders), and speech changes (slowness, hypophonia, monotony, slurring). To detect hypokinesia, tests with repetitive rapid movements are used (clenching and unclenching the fist, tapping the thumb and index finger with maximum amplitude and speed, hand pronation-supination, heel tapping on the floor). When performing the tests, attention is paid to the reduction in speed and amplitude (decrement) of repetitive movements.

Tremor. PD is characterized by a 4–6 Hz resting rotational hand tremor resembling "pill-rolling" or "coin-counting". Tremor in the extremities decreases during active movements but increases during movement of other extremities. When the process becomes generalized, tremor of the head, lower jaw, lips, tongue, and vocal cords may join. Primary development of head, voice, or writing tremor is not characteristic of PD and is more typical of essential or dystonic tremor. Resting tremor may be combined with postural tremor (tremor of outstretched hands). Unlike essential tremor, PD is characterized by re-emergent tremor, meaning the tremor appears not immediately, but several seconds after the arms are extended. Intention tremor is not characteristic of PD, although a slight vertical tremor may appear upon reaching the final goal, which is a manifestation of postural tremor (terminal). Some patients note the presence of "internal trembling" in the early stages without visible signs of tremor.

Muscle rigidity is represented by a uniform increase in tone in both flexors and extensors of the extremities and increases during repeated passive movements (the "lead-pipe" phenomenon). When tremor is superimposed, a jerky change in tone develops, resembling a "cogwheel". Rigidity predominates in the distal extremities (wrist and ankle joints) and increases during movement in the contralateral extremities. Rigidity often manifests as complaints of pain and stiffness in the shoulder joint and back pain, which may precede the appearance of other clinical symptoms of PD. In advanced stages of PD, axial muscle rigidity joins, including neck muscles, which can be detected during passive head movements. The increase in rigidity in the axial muscle group leads to the formation of a "stooped posture".

Postural disorders consist of postural abnormalities and postural instability. The stooped posture ("simian posture" / "pleader's posture") is characterized by forward flexion of the head and trunk, flexion at the knee joints, and adduction of the arms and thighs. In severe cases, a pronounced forward bend of the trunk—camptocormia—may develop. Lateral deviation of the trunk axis, known as the "Pisa syndrome", may also be observed, accompanied by scoliosis and pain syndrome. The presence of postural instability is tested using the pull test, where the physician stands behind the patient and pulls them by the shoulders after giving a warning (the patient stands with feet slightly apart). Normally, a reflexive movement occurs with lifting the arms up, leaning the trunk forward, and maintaining balance. In the early stages of PD, retropulsion can be observed, where the patient takes several steps back to maintain balance. In later stages, the patient falls in the direction of the push.

Gait disorders. The first manifestations of gait disorders in PD are: decreased stride length (microbasia), reduced walking speed due to microbasia, weakening of associated arm movements (acheirokinesia), difficulty initiating gait, and shuffling. In the advanced stage, involuntary accelerations (propulsion), shuffling gait, and the "freezing" phenomenon during walking develop. Freezing most frequently occurs during changes in action programs—when turning, overcoming an obstacle, having to pass through a narrow space, moving on an uneven surface, or during distraction. Treading in place is considered a variant of the freezing phenomenon [33].

Non-motor symptoms. Accompany all stages of the disease. Hyposmia or anosmia occurs in 80% of PD patients and often precedes the development of motor symptoms. However, the specificity of this symptom is low. In the early stages of PD, patients frequently complain of numbness and tingling.

Sleep and wakefulness disorders may be represented by: insomnia with sleep onset or sleep maintenance disorders, frequent nocturnal and/or early morning awakenings; hypersomnia (increased duration of night sleep or daytime sleepiness); parasomnia (rapid eye movement sleep behavior disorder, nightmares). Rapid eye movement sleep behavior disorder (RBD) is the most specific. This stage of sleep is characterized by the development of physiological atonia. Instead, patients with PD exhibit recurrent vocalizations, motor activity (arm flailing, leg flexion/extension, gesturing, more complex movements) reflecting the content of dreams, most often of a frightening nature. According to several studies, the frequency of RBD in PD patients reaches 60%. Furthermore, this disorder is considered one of the earliest and most specific markers of the neurodegenerative process [34].

Autonomic dysfunction is identified in 70–100% of PD patients. Disorders affect the cardiovascular, respiratory, gastrointestinal, and urogenital systems. In advanced stages of the disease, autonomic disorders significantly reduce patients' quality of life and can cause severe, life-threatening complications—pneumonia, intestinal obstruction, urinary retention.

Psychiatric disorders. PD is accompanied by a spectrum of psychiatric disorders, which include cognitive, affective, psychotic, personality, and behavioral disturbances. Depression in PD occurs in 40–50% of patients, and its prevalence is three times higher than the frequency of depression in the corresponding age population [35]. Mild to moderate depression predominates in PD. Symptoms of depression may develop several years before the onset of the disease, but more often arise at disease onset and/or during the progression of motor disorders, with the appearance of fluctuations and dyskinesias. Depressive spectrum disorders may increase against the background of a weakening effect of a single drug dose—during the "off" period. The leading symptoms of depression in PD are a depressed mood (sadness, melancholy) and an impaired ability to experience pleasure (anhedonia). Unlike depression of other etiologies, feelings of guilt, lowered self-esteem, and suicidal actions are less frequently observed in PD [36].

Cognitive impairment Cognitive impairment of varying severity is detected in at least 95% of patients with PD. As the disease progresses, cognitive impairment tends to worsen, reaching the stage of dementia in 80% of patients at advanced stages [37]. The rate of cognitive decline is especially high in individuals over 70 years of age. In younger patients and those with early-onset disease, dementia develops less frequently [38]. At early stages, cognitive impairment is predominantly represented by neurodynamic disorders in the form of bradyphrenia (slowing of mental processes, a peculiar equivalent of hypokinesia), decreased attention, and slower reaction times. Regulatory-type disorders are characteristic — difficulties with generalization, comparison, solving logical tasks, and developing action algorithms. Memory impairments are mild and caused by deficits in acquiring new material, while long-term memory remains intact. Later, visuospatial impairments may join, manifested by errors in copying drawings and disorientation difficulties. Patients with dementia frequently experience psychotic episodes in the form of visual or, much less commonly, auditory hallucinations and delusional disorders. Early stages feature illusions (perceptual distortions where, for example, a floor lamp shadow is perceived as a sitting person or animal; the illusion disappears with better lighting or putting on glasses) and "minor" (extracampine) hallucinations (the sensation that someone is standing nearby or walking past). True hallucinations then develop as realistic images of people, animals, insects, and objects. As a rule, hallucinations are not frightening, and partial insight is preserved for a long time. Hallucinations often occur in the evening or at night upon awakening. Vivid, colorful dreams serve as a peculiar precursor to visual hallucinations. Over time, hallucinations become constant and are accompanied by delusional disorders. Anti-parkinsonian drugs, especially anticholinergics, as well as increasing the doses of any anti-parkinsonian medications or their combinations, can trigger a psychotic state. Therefore, in PD patients with dementia, it is preferable to use levodopa monotherapy and its derivatives. Mental status deterioration may occur against the background of a somatic illness — concomitant pneumonia, urogenital infection, gastrointestinal disorders, dehydration, or a viral infection. The risk of psychotic disorders is higher in patients with coexisting cerebrovascular disease.

Behavioral disorders (impulse control disorders) include:

- dopamine dysregulation syndrome (development of a psychological addiction to dopaminergic drugs, leading to their uncontrolled intake);

- impulse control disorders (gambling addiction, compulsive buying/pathological shopping, hypersexuality, eating behavior disorders (hyperphagia), aggressive behavior, kleptomania, impulsive smoking);

- punding (a form of stereotyped behavior manifested by prolonged, meaningless repetitive activities, such as sorting or rearranging objects).

1.6.2. Clinical presentation of secondary parkinsonism

Neuroleptic-induced parkinsonism is one of the most common variants of secondary parkinsonism. It is characterized by subacute symptom development (within the first weeks after starting therapy or increasing the dose) manifesting as symmetric akinetic-rigidity syndrome, postural or postural-kinetic tremor (classic "pill-rolling" resting tremor is atypical), "stooped" posture, and short-stepped gait. Frequent manifestations of neuroleptic-induced parkinsonism include orobuccolingual dyskinesia ("rabbit syndrome"), akathisia, endocrine disorders, and cognitive impairment. Parkinsonian symptoms may diminish upon discontinuation of the antipsychotic, dose reduction, or administration of anticholinergic correctors (trihexyphenidyl**, biperidene**). In some patients, the course of neuroleptic-induced parkinsonism may become stationary or even progressive (in such cases, antipsychotic agents likely contribute to the earlier manifestation of an underlying latent neurodegenerative disease).

Toxic parkinsonism

Ephedrone encephalopathy manifests as spastic-hypokinetic dysarthria, postural instability with frequent falls, "rooster" gait, parkinsonian symptoms (hypokinesia, hypomimia, muscle rigidity), dystonia (most commonly of the feet with toe curling, as well as spasmodic torticollis, blepharospasm, and a "dystonic smile"), myoclonus, bradyphrenia, and hypersomnia. Resting tremor is atypical. Symptoms of pyramidal and cerebellar insufficiency are frequently identified. Autonomic dysfunction (sialorrhea, impotence, vasomotor disorders) is noted in many patients. Early in the development of intoxication, emotional lability, euphoria, aggressiveness, and rapid fatigue may appear. Subsequently, apathy, depression, and subcortical-frontal cognitive impairment develop. Ephedrone-induced parkinsonism is characterized by a steadily progressive disease course with worsening symptoms.

The toxic effect of pesticides can manifest as postural-kinetic tremor, akinetic-rigidity syndrome, postural instability, dystonia, and cognitive decline.

Cyanide poisoning, particularly via inhalation or oral ingestion, is accompanied by the rapid development of non-specific symptoms including headache, nausea, hyperesthesia, respiratory disturbances, seizures, and symmetric parkinsonian symptoms. Severe cases involve impaired consciousness, cardiac arrhythmias, coma, and death.

Vascular parkinsonism

Vascular parkinsonism is characterized by the development of symmetric akinetic-rigidity syndrome, postural-kinetic tremor, less commonly resting tremor, formation of a flexed posture of the trunk, and gait disturbances (decreased step height and length, shuffling or marche à petits pas, difficulty initiating gait, freezing, propulsion/retropulsion, and ahakinesia). Frequent falls appear in the later stages. Unlike Parkinson's disease, the following are atypical: hyposmia, REM sleep behavior disorder, asymmetry of symptoms at disease onset, high efficacy of dopaminergic drugs and their derivatives, and the development of fluctuations and dyskinesias. It is important to distinguish vascular parkinsonism from symptoms of frontal gait disorder (lower body parkinsonism). In frontal gait disorder, hypokinesia and rigidity are absent, including in the lower extremities (spastic-type increases in muscle tone are more typical), tremor is absent, the base of support during walking is widened, feet are angled outward ("Charlie Chaplin gait"), arms actively swing during walking, and falls develop significantly earlier.

The course of vascular parkinsonism may be stationary or show partial symptom regression, as well as a progressive stepwise (fluctuating) course (alternating periods of progression, stabilization, and partial regression) [5, 6].

1.6.3. Clinical presentation of parkinsonism in multisystem neurodegenerative diseases

Dementia with Lewy bodies. The most common cause of the combination of parkinsonism and dementia. The clinical picture consists of steadily progressing cognitive, psychotic, motor, autonomic, and emotional-affective disorders. Most frequently, the disease debuts with neurodynamic and executive cognitive impairments: bradyphrenia, reduced attention and reaction speed, aspontaneity, as well as impaired planning, abstraction, comparison, and ability to perform complex tasks. It is characterized by early reduction in speech fluency (primarily phonemic fluency, followed by semantic fluency) and the development of visuospatial disorders, which are initially detected during visuospatial function tests and later lead to spatial disorientation difficulties. Memory impairments remain moderate for a long time and are caused by attention deficits during information encoding, as well as difficulties in retrieving stored information due to subcortical-frontal pathway dysfunction. As dementia with Lewy bodies progresses, a mixed subcortical-cortical cognitive defect forms with profound impairments in executive and visuospatial functions [10, 39].

Visual hallucinations may be the initial symptoms of dementia with Lewy bodies (in 10–20% of patients) and occur in 80% of patients at later stages [40]. Hallucinations are most often represented by images of animals, people, plants, or objects. Visual hallucinations may be accompanied by auditory, tactile, and olfactory hallucinations, which are usually related to the visual images. Hallucinations are frequently combined with illusions and serve as the basis for the development of delusions (delusions of persecution, theft, infidelity, or being harmed). Hallucinatory and paranoid symptoms worsen in the evening and nighttime hours.

Parkinsonian syndrome may precede the onset of cognitive dysfunction, develop in parallel with it, or follow it. When dementia with Lewy bodies begins with parkinsonian symptoms, cognitive disorders join within no more than 1 year, which is a formal criterion for differential diagnosis between dementia with Lewy bodies and Parkinson's disease dementia [41]. Parkinsonian syndrome in dementia with Lewy bodies is characterized by: symmetry of development, rapid progression of axial motor disorders (hypomimia, truncal bradykinesia, gait disturbances with freezing, stooped posture, dysphonia, dysphagia). Resting tremor is atypical. Symmetric postural-kinetic tremor may develop, and dystonic disorders (blepharospasm, spasmodic torticollis) and myoclonus are quite frequently added. The efficacy of dopaminergic drugs and their derivatives is low. Similar to patients with Parkinson's disease, rapid eye movement (REM) sleep behavior disorder (verbal and motor activity) and a wide range of autonomic disorders (constipation, urinary disturbances, erectile dysfunction, blood pressure and heart rate variability, orthostatic hypotension, syncope) are characteristic.

A hallmark feature of dementia with Lewy bodies is fluctuations in mental status, observed in 80% of patients, often as early as the early stage of the disease. Fluctuations represent distinct oscillations in mental and motor activity lasting from several minutes to several days. During this period, the patient becomes unresponsive, akinetic, and ceases communication.

Patients with dementia with Lewy bodies are distinguished by heightened sensitivity to antipsychotic agents with the rapid development of akinesia, autonomic dysfunction, and neuroleptic malignant syndrome-like confusion.

Multiple system atrophy. The main symptoms of multiple system atrophy are parkinsonism, cerebellar and pyramidal signs, and autonomic disorders. Depending on the predominance of particular syndromes, two main clinical variants of multiple system atrophy are distinguished: parkinsonian type (striatonigral degeneration) and cerebellar type (olivopontocerebellar atrophy). The average age of onset is between 50 and 60 years [42, 43].

Autonomic failure either precedes the development of motor disorders or joins within the first 2 years of the disease. Autonomic dysfunction includes: 1) orthostatic hypotension with a drop in systolic blood pressure of more than 30 mm Hg and/or diastolic (≥ 15 mm Hg) within 3 minutes of assuming an upright posture. Clinically, orthostatic hypotension manifests as complaints of dizziness, darkening of the vision, instability, tinnitus, and syncope. Orthostatic hypotension is exacerbated by prolonged recumbency, heavy meals, alcohol consumption, and dehydration. Multiple system atrophy is also characterized by supine hypertension and a "fixed pulse" (heart rate does not change depending on horizontal and vertical positions); 2) neurogenic bladder dysfunction; 3) sexual dysfunction; 4) gastrointestinal motility disorders (constipation, fecal incontinence); 5) Raynaud's phenomenon; 6) poor tolerance to hot weather.

Parkinsonism symptoms are combined with pyramidal signs (pathological plantar reflexes, hyperreflexia, pseudobulbar syndrome) and cerebellar symptoms (impaired statics, coordination deficits, dysarthria, nystagmus). In the cerebellar subtype of MSA, coordination impairments are the primary and dominant symptoms, whereas in the parkinsonian variant, they develop after 4–5 years.

Unlike PD, parkinsonism symptoms in MSA are characterized by symmetrical development, absence of resting tremor, rapid progression rate, and low efficacy of dopamine and its derivatives. An early sign of MSA is rapid eye movement sleep behavior disorder (RBD). Difficulty falling asleep, frequent awakenings, respiratory stridor, sleep apnea, and daytime sleepiness are characteristic. Unlike other types of atypical parkinsonism, cognitive dysfunction in MSA does not reach the level of dementia.

Progressive supranuclear palsy. PSP accounts for 2–5% of parkinsonism cases. There are several subtypes of PSP. The classic variant of PSP is Richardson's syndrome, characterized by vertical gaze palsy, pseudobulbar syndrome, rigidity, akinesia, postural instability, and cognitive impairment. Unlike typical PD, the parkinsonian syndrome in PSP is characterized by: symmetry of parkinsonism symptoms, absence of classic rotatory resting tremor, greater prominence of hypokinesia in the axial regions leading to trunk extension, retrocollis, a wide-based unstable gait with backward falls; response to levodopa is limited or absent, and dyskinesias are not characteristic. PSP is characterized by a rapid progression rate. Average life expectancy is 5–8 years. Marked immobility and dementia develop [44, 45]. Pneumonia (respiratory infection, respiratory failure, and aspiration pneumonia) is the most frequent direct cause of death, significantly more often than in PD [46].

The most characteristic feature of PSP is oculomotor disorders in the form of vertical gaze palsy, predominantly downward, with preserved horizontal movements. In the early stages of the disease, slowing, hypometria, and impaired smoothness of vertical saccades, as well as loss of suppression of the vestibulo-ocular reflex, can be noted. Later, horizontal gaze abnormalities join, followed by total ophthalmoplegia. Already 1–2 years after disease onset, pronounced pseudobulbar syndrome develops with dysarthria, dysphagia, and primitive reflexes. Gait disturbances with frequent falls (predominantly backward) manifest early, already within the first year of the disease. Late stages are characterized by dystonia of various localizations—limbs, trunk, blepharospasm—which, as a rule, are not associated with dopaminergic medication intake. Cognitive impairments steadily progress along with motor symptoms, up to the development of dementia.

Other clinical subtypes of PSP include the parkinsonian variant of PSP, and variants with initial predominance of oculomotor dysfunction or postural instability.

Corticobasal degeneration (CBD) is characterized by a progressive asymmetric akinetic-rigid syndrome, limb dystonia, higher cortical function impairment, and the "alien hand" phenomenon. Along with bradykinesia, rigidity, and postural-kinetic tremor, CBD is characterized by the rapid development of gait disturbances (frontal-type gait apraxia/dysbasia) and postural instability with backward falls. Dystonia is detected in 55–83% of patients and is focal or segmental in nature. The most common dystonically postured arm features adduction at the shoulder joint and flexion at the elbow and wrist joints. In advanced stages, focal myoclonus, dysarthria, dysphagia, and pyramidal signs are frequently detected. The parkinsonian syndrome is resistant to dopamine and its derivatives.

A specific symptom of CBD is the "alien hand" phenomenon, manifested by a feeling of detachment of the limb and its involuntary motor activity with an inability to participate in voluntary activity. Patients with closed eyes cannot tell where the hand is, and examination reveals impairments of proprioceptive and complex forms of sensation. The "alien hand" is characterized by spontaneous motor activity—lifting the hand up (levitation), feeling objects, rumpled clothing, repeating movements of the healthy hand, or the "alien hand" interfering with the actions of the other hand.

The spectrum of higher cortical function disorders is variable. Ideomotor apraxia is the most common (in 80% of cases), where the execution of actions upon command, with imaginary objects, or the repetition of a just-demonstrated movement is impaired. Luria's test can be used to detect ideomotor apraxia. Oral apraxia (inability to lick lips, place the tongue between the teeth), as well as eyelid opening apraxia and gait apraxia, are also characteristic. Other disorders include aphasia (dynamic, semantic) and executive dysfunction.

It should be noted that corticobasal syndrome occurs in a number of other neurodegenerative diseases—frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease [11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of PD is established based on clinical data. Since differential diagnosis between PD and other multisystem degeneration disorders is difficult in early stages, repeat patient evaluation is recommended.

To date, the diagnosis of Parkinson's disease (PD) is established based on the criteria of the International Parkinson and Movement Disorder Society (MDS) [47, 48]. It should be noted that the assessment of motor manifestations of PD should be performed as described in the MDS-UPDRS.

The main prerequisite for diagnosing PD is the presence of parkinsonism, namely, a combination of bradykinesia with resting tremor and muscular rigidity.

Supporting criteria:

• Clear and marked response to dopaminergic therapy (meaning an unambiguous return to normal or near-normal lifestyle after therapy initiation or the presence of fluctuations);
• Presence of levodopa-induced dyskinesias;
• Resting tremor documented on examination;
• Presence of olfactory loss or cardiac sympathetic denervation on iodine-123-metaiodobenzylguanidine ([123I]MIBG) myocardial scintigraphy [123I]

Absolute exclusion criteria:

• Unequivocal cerebellar signs;
• Downward vertical supranuclear gaze palsy or slowing of vertical saccades;
• Diagnosis of possible behavioral variant frontotemporal dementia (bvFTD) or primary progressive aphasia (PPA) established according to established diagnostic criteria within the first 5 years of the disease;
• Parkinsonism limited to the lower half of the body for more than 3 years.
• Treatment with drugs known to induce drug-induced parkinsonism (see Drug-induced parkinsonism);
• Absence of clear response to high-dose therapy with dopamine and its derivatives (≥ 600 mg/day);
• Impairment of complex forms of sensation, limb ideomotor apraxia, progressive aphasia;
• Preserved presynaptic dopaminergic pathways on functional neuroimaging (this item does not imply mandatory testing for all patients);
• Alternative diagnosis established that explains the patient's parkinsonism and other symptoms better than PD; this alternative diagnosis is established based on expert medical evaluation or has other documentary confirmation.

Red flags:

• Rapid progression of gait impairment resulting in wheelchair dependence within 5 years from disease onset;
• Complete absence of progression of motor and other symptoms over 5 or more years (unless maintained by adequate therapy);
• Early development of bulbar dysfunction: severe dysphonia, or dysarthria, or severe dysphagia (requiring minced food, nasogastric tube feeding, or gastrostomy) within 5 years of disease onset;
• Inspiratory respiratory abnormalities: daytime or nighttime inspiratory stridor or frequent inspiratory sighs;
• Severe autonomic dysfunction within the first five years of disease onset: either orthostatic hypotension, defined as a drop in systolic BP of at least 30 mmHg or diastolic BP of at least 15 mmHg within 3 minutes of standing in the absence of dehydration, antihypertensive medications, or other diseases, or severe urinary retention or incontinence within the first 5 years of the disease course (excluding stress incontinence of small amounts of urine or incontinence due to prolonged standing in women). In men, urinary retention must not be related to prostate disease and must be combined with erectile dysfunction;
• Recurrent falls (more than 1 time per year) due to balance impairment within 3 years of disease onset;
• Pronounced anterocollis or limb contractures within 10 years of disease onset;
• Absence of common non-motor symptoms of PD for 5 years or more: sleep disorders (frequent awakenings, excessive daytime sleepiness, rapid eye movement sleep behavior disorder [RBD] symptoms), autonomic dysfunction (constipation, daytime urinary incontinence, orthostatic hypotension), hyposmia, or psychiatric disorders (depression, anxiety, or hallucinations);
• Pyramidal signs not explained by other causes (central paresis or pathological hyperreflexia of deep reflexes, excluding mild reflex asymmetry or an isolated Babinski sign);
• Bilateral symmetrical parkinsonism. The patient or caregivers report bilateral symptom development without predominance of one side; examination also reveals no asymmetry.

Clinically established PD diagnosis requires:

• absence of absolute exclusion criteria;
• at least 2 supportive criteria;
• absence of red flags.

Clinically probable PD diagnosis requires:

• absence of absolute exclusion criteria;
• in the presence of red flags – presence of supportive criteria (if 1 red flag is present – 1 supportive criterion is needed, if 2 red flags are present – 2 supportive criteria);
• presence of no more than 2 red flags.

Parkinsonism syndrome can be manifested by other diseases besides PD. Other conditions should be suspected in the presence of red flags and PD exclusion criteria [47, 48]. A brief description of the main nosological forms of diseases manifesting with parkinsonism is given in the table below. Potentially curable conditions are highlighted in italics [48]:

Table 1. Main diseases manifesting with parkinsonism syndrome

Criteria for establishing a clinical diagnosis of secondary parkinsonism and parkinsonism in other multisystem neurodegenerative diseases are given in Appendix A3. The parkinsonism diagnostic algorithm is presented in Appendix B.

2.1 Complaints and Anamnesis

The main complaints and anamnesis are described in subsection 1.6 "Clinical Presentation". Since the diagnosis is made based on the aforementioned MDS criteria, it is important to conduct targeted questioning when interviewing the patient and accompanying persons in order to identify red flags. It should also be ascertained whether the patient is taking antiparkinsonian therapy, and if so, which drugs and for how long. The time of the last medication intake should be clarified.

The presence of non-motor disorders should also be assessed: olfactory disturbances, sleep disorders (especially RBD), daytime sleepiness, tendency to constipation, urinary frequency, erectile dysfunction, orthostatic hypotension, affective and cognitive impairment, as well as the presence of hallucinatory and delusional symptoms [48, 50].

Comments: Cognitive and affective disorders capable of affecting the ability to critically assess one's own condition are common in PD [53, 54]. Due to the fact that anamnestic data play a valuable role in the diagnosis and treatment of PD, the role of informants in clinical practice should not be underestimated.

Comments: The patient's quality of life and daily activity not only reflect the patient's physical and mental well-being, but also serve as guidelines for monitoring the effectiveness of therapy. To quantify these indicators, part I of the MDS UPDRS scale "Non-motor aspects of daily living (nM-EDL)" is used.

2.2 Physical Examination

The main data are presented in Section 1.6 "Clinical Presentation". Since the diagnosis is made based on the above MDS criteria, it is important to pay attention to potential exclusion criteria and red flags during physical examination. It should also be noted that the motor function examination is carried out similarly to that described in the MDS-UPDRS scale (Appendix G1). A complete neurological examination is performed on all patients with suspected PD. It should also be noted whether the examination is performed against the background of antiparkinsonian therapy.

During the interview and physical examination, the patient's speech (volume, modulation, clarity), facial expression, and general motor activity are assessed. Next, the presence of muscle rigidity, resting tremor, postural tremor, and kinetic tremor is evaluated. Motor activity is also assessed through specific tests: hand pronation-supination tests and foot-tapping tests. Furthermore, it is mandatory to ask the patient to stand up and walk at least 10 meters. During this, the clinician should evaluate how the patient rises from a chair or armchair, their gait (stride length, foot lift height, turning speed, arm swing amplitude, and the presence of freezing), and posture. A postural stability test, or Thévenard's test, is performed. It is also recommended to screen for orthostatic hypotension during the examination [47, 48].

2.3 Laboratory Diagnostics

Comments: Currently, there are no reliable laboratory biomarkers for PD. However, the burden of comorbid conditions (e.g., diabetes mellitus and arterial hypertension) significantly impacts patients' quality of life, disease prognosis, and therapeutic management [58, 59].

Comments: According to studies, < 10% of all PD cases are caused by mutations in known genes; therefore, genetic testing allows for a definitive diagnosis in a small number of patients. Since no specific treatment currently exists for genetically determined PD, the purpose of these studies is to determine the prognosis of the disease course and the risk of its occurrence in relatives. In autosomal dominant inheritance, it is advisable to screen for mutations in the genes SNCA, LRRK2, GBA (for populations characterized by a high frequency of mutations in these genes). In cases of early-onset disease and suspicion of autosomal recessive inheritance, screening of the genes PARK2, PINK1, DJ-1 is advisable [52].

2.4 Instrumental Diagnostics

Comments: Although neuroimaging is frequently ordered for PD patients, clinical evaluation remains the primary diagnostic method.

If a patient's clinical presentation differs from classical PD, neuroimaging may be useful in revealing relatively specific features of MSA (atrophic changes and putaminal hyperintensity, the "hot cross bun" sign, etc.) (Appendix A3) or PSP ("hummingbird sign", dilation of the third ventricle) (Appendix A3), as well as structural abnormalities (hydrocephalus, tumors, etc.). Some authors recommend supplementing standard MRI sequences with the T2*/SWI sequence on 3.0 Tesla or higher field strength scanners, which evaluates the structures of the substantia nigra pars compacta (nigrosome-1), normally displaying the characteristic "swallow tail" appearance; the "swallow tail" sign disappears even in the early stages of PD [48, 62].

Comments: Substantia nigra hyperechogenicity (SNH) on transcranial sonography is observed in 90% of PD patients and is associated with increased iron content in the substantia nigra. In most studies, an area of > 0.2 cm² is accepted as the threshold value for SNH. The specificity of this method is approximately 75%, which is why its use must be complemented by other diagnostic procedures. [48, 63].

Comments: Brain PET-CT and SPECT using ligands tropic to the nigrostriatal system are methods unavailable in routine clinical practice [64, 65].

2.5 Other Procedures

Comments: An acute pharmacological challenge test with dopaminergic drugs and their derivatives is performed in patients who have not previously received therapy or have received it in low doses (up to 300 mg/day) and consists of a single intake of 250 – 1000 mg of dopaminergic drugs and their derivatives, followed by an evaluation of the motor sphere (Part III of the MDS UPDRS scale) before and one hour after administration. A test is considered positive if there is an improvement of at least 30% on the scale. Currently, instead of an acute pharmacological challenge test, it is recommended to evaluate the efficacy of therapy 1 – 3 months after initiating antiparkinsonian treatment [67].

Comments: Cognitive impairment (CI) is one of the most common non-motor symptoms of PD. The presence of mild cognitive impairment in the early stages of PD is a predictor of dementia development. A number of neuropsychological scales are used to detect CI, the most convenient of which in clinical practice are the Mini-Mental State Examination (MMSE) (Appendix G2) and the Montreal Cognitive Assessment scale (Appendix G3) [48, 54].

Comments: Sleep disturbances are characteristic of PD and include insomnia, hypersomnia, and parasomnia disorders. These disorders affect quality of life, and REM sleep behavior disorder (RBD) occurs in a large number of patients and can often cause injuries to either the patients themselves or their family members. Studies also show that they can be early (non-motor) signs of PD and predictors of a more severe disease course. The MDS-UPDRS scale (Appendix G1) can be used to detect them [48, 66 – 68].

Comments: Affective disorders in PD are a factor that reduces patients' quality of life and requires management. In severe cases, their presence reliably worsens the prognosis of the disease. The Hospital Anxiety and Depression Scale (HADS) (Appendix G4) is used to detect them [48, 71, 72].

Comments: Psychotic and behavioral disorders in PD are a factor that reduces patients' quality of life and requires management. They reliably worsen the prognosis of the disease. The MDS-UPDRS scale (Appendix G1) can be used to detect them.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The main areas of treatment for Parkinson's disease (PD) are: 1) neuroprotective therapy, aimed at slowing down/stopping the neurodegeneration process; 2) symptomatic therapy, which reduces the main symptoms of the disease by correcting the neurotransmitter imbalance occurring in the brain; 3) surgical treatment; 4) rehabilitation.

3.1 Conservative treatment of Parkinson's disease

The main antiparkinsonian drugs are presented in Table 2.

Table 2. Antiparkinsonian symptomatic therapy for Parkinson's disease

3.1.1. Treatment of early stages of Parkinson's disease

3.1.1.1. Neuroprotective, neuroreparative, and disease-modifying therapy

Comments: Currently, there is no conclusive evidence of the efficacy of drugs with neuroprotective, neuroreparative, and disease-modifying effects. For certain groups of symptomatic drugs (monoamine oxidase (type B) inhibitors, dopamine receptor agonists, adamantane derivatives**, dopa and its derivatives), there is indirect evidence of neuroprotective potential.

Study data are contradictory and do not allow for a definitive decision. Several studies have shown that selegiline prescribed in the early stages of PD delays the need for therapy with dopa and its derivatives by an average of several months, which may be due to its symptomatic effect [74, 75]. The results of the TEMPO and ADAGIO studies with delayed initiation of rasagiline are consistent with the potential modifying effect of this drug at a dose of 1 mg/day, although the ADAGIO study data were recognized as ambiguous [76 - 79]. There is no conclusive data on the disease-modifying effect of DRAs [80 - 82]. A study of the dopamine receptor agonist pramipexole** with a delayed start (PROUD) revealed no signs of a disease-modifying effect of the drug [80].

Two placebo-controlled studies, including one study with a delayed start, failed to demonstrate conclusive evidence of a disease-modifying effect of dopa and its derivatives [83 - 86]. Nevertheless, one low-certainty study showed a positive effect of dopa and its derivatives on survival [87]. Regarding anticholinergic agents and adamantane derivatives**, there are no analyzable studies indicating solely a neuroprotective effect of the drug. Medications without a symptomatic effect in class I - II controlled studies [88, 89, 90], alpha-tocopherol acetate [74] did not show a modifying effect on the course of the disease. Clinical studies of drugs with new mechanisms of action are currently underway.

3.1.1.2 Initial symptomatic therapy

Monoamine oxidase (type B) inhibitors, DRAs, adamantane derivatives, anticholinergic agents, and dopa and its derivatives can be used as initial therapy for PD. The strategy of symptomatic therapy for patients with PD depends on the patient's age, disease stage, disabling symptoms, and occupational and daily activities (Appendix B). The balance between treatment efficacy and safety, symptomatic efficacy, and the ability to postpone the development of therapy complications must be considered.

Comments: It has not been proven that the early initiation of dopaminergic therapy leads to more favorable long-term outcomes. The daily dose of drugs is selected gradually, by titration or slow dose escalation (Appendix A3).

Comments: Subsequently, if the initially prescribed drug at a medium therapeutic dose does not provide the expected effect, combination therapy is initiated (simultaneously prescribing or increasing the dose of no more than one drug) [73, 74, 79].

Comments: It is necessary to prescribe DRAs as initial therapy to younger patients, thereby reducing the need for dopa and its derivatives and delaying the development of motor fluctuations and dyskinesias. DRAs reduce the need for dopa and its derivatives, thereby delaying the development of motor fluctuations and dyskinesias.

Comments: In addition to adequate control of motor impairments, DRAs have been found to have an antidepressant effect, which is important given the high prevalence of depressive syndrome in PD. The daily dose of DRAs is selected gradually, by titration or slow dose escalation (Appendix A3).

Comments: The efficacy and safety of various DRA drugs at appropriate doses are approximately equal [98 - 100]; therefore, the drug is chosen based on individual sensitivity, taking into account the side effect profile, additional pharmacological actions, and tolerability. There is no evidence that extended-release DRAs have an additional effect or are safer, but in some cases, e.g., in gastrointestinal diseases, they may be preferred. When prescribing DRAs, regular monitoring is required for complications associated with lower limb edema, daytime somnolence, hallucinations, and impulse control disorders.

In controlled trials in patients with early-stage PD, dopamine agonists demonstrated greater efficacy compared to placebo [101 - 109]. However, levodopa and its derivatives are more effective than dopamine agonists. As the disease progresses, the proportion of patients able to remain on dopamine agonist monotherapy progressively decreases to 20% after 5 years of treatment [82, 85, 88, 110 - 116]. In randomized trials, once-daily extended-release formulations of pramipexole** and ropinirole demonstrated similar efficacy and tolerability compared to standard formulations [117, 118]. Dopamine agonists are effective in correcting parkinsonian symptoms in patients already receiving therapy with levodopa and its derivatives [119 - 141]. In small controlled trials, early use of dopamine agonists was shown to reduce the incidence of motor complications compared to the use of levodopa and its derivatives [82]. In the only published study comparing ropinirole with bromocriptine**, no differences were found in the incidence of dyskinesias after 3 years [114]. Dopamine agonists were associated with a higher incidence of hallucinations, daytime sleepiness, and lower extremity edema compared to levodopa and its derivatives [81, 83, 92, 94 - 95]. When high doses of dopamine agonists are used, 15% of PD patients develop impulse control disorder [95]. In patients with cognitive impairment, the likelihood of developing hallucinosis and obsessive-compulsive disorder with dopamine agonists is higher; therefore, a brief neuropsychological assessment is advisable when prescribing dopamine agonists. Pramipexole** and extended-release ropinirole helped reduce nighttime symptoms of Parkinson's disease and improved sleep quality [139]. In a comparative randomized trial of piribedil** and pramipexole**, the former showed a lower incidence of daytime sleepiness with no significant differences in therapeutic effect size.

Comments: In a class I study, combination therapy with levodopa+entacapone+[carbidopa] in PD patients without fluctuations achieved a higher quality of life compared to levodopa/carbidopa**. However, in the STRIDE–PD study (class I), the time to the onset of dyskinesias in the group of patients receiving levodopa+entacapone+[carbidopa] was significantly shorter than in the group of patients receiving levodopa+carbidopa** with placebo, while no differences were noted regarding the development of the "wearing-off" phenomenon [146].

Comments: The use of anticholinergics (trihexyphenidyl**, biperiden**) is limited by their negative impact on cognitive functions and the potential development of neuropsychiatric disorders [149]. Contraindications for prescribing anticholinergics include angle-closure glaucoma, tachyarrhythmia, and severe prostatic hyperplasia in men. Sudden discontinuation of anticholinergics may be accompanied by withdrawal syndrome, so drug withdrawal should be gradual.

3.1.1.3. Subsequent adjustment of symptomatic therapy

Comments: Choose a tremor corrector taking into account the risk of its side effects. The decision to prescribe anticholinergics as a tremor corrector is made after neuropsychological testing and the exclusion of cognitive impairment. The use of anticholinergics is limited by their negative impact on cognitive functions and the potential development of neuropsychiatric disorders [149]. Contraindications for prescribing anticholinergics include angle-closure glaucoma, tachyarrhythmia, and severe prostatic hyperplasia in men. Sudden discontinuation of anticholinergics may be accompanied by withdrawal syndrome, so drug withdrawal should be gradual.

3.1.2. Treatment of the advanced stage of Parkinson's disease

The advanced stage of Parkinson's disease (corresponding to stages 3 - 4 on the Hoehn and Yahr scale) is characterized by an increase in the severity of motor and non-motor symptoms, which is associated with the relentless progression of the disease and the loss of a significant portion of nigrostriatal neurons. At this stage, severe motor fluctuations (oscillations in the response to levodopa and its derivatives) and dyskinesias (excessive movements at the peak of the effect of levodopa and its derivatives) intensify, leading to limitations in daily activities. At this stage, patients experience a significant prolongation of "off" periods with increasing bradykinesia, the appearance of freezing, severe hypophonia, and other symptoms. Among non-motor symptoms, there is a significant increase in pain manifestations, anxiety, depression, apathy, and cognitive impairment.

The treatment of advanced stages of Parkinson's disease involves the correction of both motor symptoms and pharmacotherapy complications that arise as the disease progresses. In addition to motor deficits, the advanced stage requires the assessment and correction of a wide range of non-motor symptoms (cognitive, affective, psychotic, autonomic manifestations, sleep disorders), which are presented in the relevant sections.

3.1.2.1. Correction of the "end-of-dose wearing-off" phenomenon of dopaminergic drugs and their derivatives

Comments: Shortening the intervals between doses by increasing the frequency while maintaining the total daily dose. This approach, firstly, helps reduce the severity of motor fluctuations by shortening the time between doses of levodopa and its derivatives, and may also help reduce the risk of drug-induced dyskinesias by keeping the patient on a relatively small single dose for a longer period. Although, due to the difficulty of conducting placebo-controlled trials, the evidence levels and grades are not sufficiently high, this approach is justified for empirical reasons and can be recommended for virtually all patients in the advanced stage of Parkinson's disease.

Comments: Adding entacapone to levodopa and its derivatives prolongs the effect of a single dose and helps reduce motor fluctuations. The substitution is performed at a dose equivalent to the two-component drug (the triple combination drug levodopa+entacapone+[carbidopa] is available in levodopa doses of 50/100/150 and 200 mg). A single-dose combination of the triple and double combination drugs is possible, which helps prolong the effect of a single dose.

Comments: Controlled studies have demonstrated the ability of rasagiline at a dose of 1 mg daily to reduce "off" periods and prolong the effect of a single dose by an average of 1 hour. The drug provokes less psychotic symptomatology [158 - 161].

Comments: The addition of a dopamine receptor agonist helps reduce the "off" period by more than 1 hour. Ergot dopamine receptor agonists are not recommended for treating advanced stages due to the high risk of side effects, which outweighs the expected efficacy. The decision to add a dopamine receptor agonist to the therapy of patients with advanced Parkinson's disease should be made only after assessing cognitive status and the risk of psychotic symptoms. In cases of pronounced cognitive impairment and even "minor" psychotic symptoms, the addition of this group of drugs is not recommended.

Comments: There is no data on the superiority of one dopamine receptor agonist over others. In some cases, if a dopamine receptor agonist shows insufficient efficacy and poor tolerability, switching to another drug in equivalent doses may be recommended. A day-to-day switch based on dose equivalence can be used: 1 mg of pramipexole** = 4 mg of ropinirole and 100 mg of piribedil**.

Comments: There is no conclusive evidence regarding the advantages of prolonged-release formulations over standard dopamine receptor agonist formulations, and this remains at the physician's discretion. In some cases, prolonged-release formulations may offer advantages, though not in clinical efficacy. Once-daily dosing may ensure therapy compliance and is more convenient for certain patients. Data on efficacy or safety advantages among different formulations are not sufficiently convincing.

3.1.2.2. Correction of severe motor fluctuations and dyskinesias when available combinations of antiparkinsonian drugs are ineffective

In advanced Parkinson's disease (stages 4 and 5 on the Hoehn and Yahr scale) with pronounced motor fluctuations and dyskinesias when available combinations of antiparkinsonian drugs are ineffective, the installation of a levodopa/carbidopa intestinal gel pump is recommended.

Indications for prescribing levodopa/carbidopa intestinal gel therapy in cases of insufficient control of motor symptoms against the background of adequate oral therapy in the advanced stage, according to expert consensus [190, 122]:

- intake of dopa and its derivatives at least 5 times a day;

- at least 2 hours of "off" time during the day;

- at least 1 hour of disabling dyskinesias per day.

A high level of daily activity during the "on" period should be maintained.

Comments: In the advanced stage, a decrease in the efficacy of oral formulations of dopa and its derivatives and other pill-based antiparkinsonian drugs is observed, because with disease progression and changes in gastric motility, dopa and its derivatives cease to reach the small intestine for direct absorption. The gel is administered using a portable pump directly into the lumen of the duodenum or the upper jejunum via a permanent duodenal tube placed by percutaneous endoscopic gastrostomy [190 - 192].

Comments: The use of levodopa/carbidopa intestinal gel therapy leads to a statistically significant increase in hours without disabling dyskinesias in patients compared to optimized oral therapy [194]. Levodopa/carbidopa intestinal gel therapy is statistically significantly more effective in terms of hours without motor fluctuations compared to the standard oral levodopa/carbidopa formulation [194]. Prolonged use of levodopa/carbidopa intestinal gel promotes a statistically significant, sustained reduction in the severity of motor and non-motor symptoms, reducing "off" periods by an average of 4.2 – 5.3 hours and dyskinesias by an average of 1.7 hours per day [195, 196]. The use of levodopa/carbidopa intestinal gel therapy reliably improves quality of life [197].

Comments: see the relevant section "Neurosurgical treatment of Parkinson's disease".

3.1.2.3. Correction of delayed onset or absence of effect of a single dose of dopa and its derivatives

Comments: Studies on the clinical efficacy of correcting the delayed onset or absence of effect of a single dose of dopa and its derivatives have not been conducted; however, some conclusions can be drawn from expert recommendations.

3.1.2.4. Correction of the "on-off" phenomenon and inconsistent single-dose effect of dopa and its derivatives

Comments: The same approaches are used as for correcting the "wearing-off" phenomenon of dopa and its derivatives (see subsection 3.1.2.1.) and the delayed onset or absence of effect of a single dose of dopa and its derivatives (see subsection 3.1.2.3.).

3.1.2.5. Correction of unpredictable fluctuations in the effect of a single dose of dopa and its derivatives

Comments: see the relevant section "Neurosurgical treatment of Parkinson's disease".

Comments: The same approaches are used as for correcting the "wearing-off" phenomenon of dopa and its derivatives (see subsection 3.1.2.1.) and the delayed onset or absence of effect of a single dose of dopa and its derivatives (see subsection 3.1.2.3.).

3.1.2.6. Correction of freezing of gait phenomenon

Freezing of gait is a unique phenomenon encountered in patients with Parkinson's disease, characterized by sudden, brief episodes of inability to initiate stepping or continue movement.

Comments: see the corresponding section "Medical Rehabilitation in Parkinson's Disease".

3.1.2.7. Correction of peak-dose dyskinesias

Comments: The possibility of reducing the risk of dyskinesias through long-term use of higher doses of DRAs instead of escalating the dose of dopaminergic drugs and their derivatives has been studied primarily with ropinirole, which provides the most significant range of recommended daily doses (from a minimum effective dose of 8 mg to a maximum of 24 mg daily), and these studies were exclusively open-label in design. Given the risk of provoking psychotic and cognitive impairments, the use of maximum doses should be carried out only with careful patient selection and mandatory neuropsychological evaluation.

Comments: Increasing the number of doses allows the total daily amount of the medication to be distributed while reducing the single dose of dopaminergic drugs and their derivatives. Although the levels of reliability and grades of evidence are not sufficiently high due to the impossibility of conducting placebo-controlled trials, this approach is effective and can be recommended for virtually all patients with peak-dose drug-induced dyskinesias.

Comments: The addition of amantadine** to therapy with dopaminergic drugs and their derivatives at a dose of 200 mg per day significantly reduces the manifestations of drug-induced dyskinesias. The decision to add amantadine** to therapy should be made only after neuropsychological testing and assessment of cognitive status. In cases of pronounced cognitive impairment with a risk of psychosis, amantadine** therapy is not recommended.

Comments: The possibility of reducing drug-induced dyskinesias with this therapy has been demonstrated in a small number of studies [214 - 218]. Given that clozapine is an atypical antipsychotic agent that can itself provoke parkinsonian symptoms, its use is only possible in severe, disabling dyskinesias when the expected benefit outweighs the risk and the potential for using other methods has been entirely exhausted.

Comments: see the relevant section "Neurosurgical treatment of Parkinson's disease".

3.1.2.8. Correction of diphasic dyskinesias

Comments: Increasing the single dose of dopaminergic drugs and their derivatives while reducing the frequency of administration helps make dyskinesias manageable and allows the application of peak-dose dyskinesia correction approaches. Although placebo-controlled studies are not feasible, this approach can be recommended for patients with drug-induced diphasic dyskinesias.

Comments: see the relevant section "Neurosurgical treatment of Parkinson's disease".

3.1.2.9. Correction of off-period dystonia

Comments: increasing the dose of DRAs or dopaminergic drugs and their derivatives will prolong the "on" period and thereby reduce the likelihood of developing "off" period dystonia. Although placebo-controlled trials are not feasible, this approach can be recommended to patients.

Comments: see the relevant section "Neurosurgical treatment of Parkinson's disease".

Comments: Studies on the clinical efficacy of injecting botulinum toxin type A** into muscles involved in hyperkinesia in patients for the correction of focal "off" period dystonia have not been conducted; however, certain conclusions can be drawn from expert recommendations. For cervical dystonia, effective doses range from 50 to 150 units, and for painful foot dystonia, approximately 100 units. The duration of the drug's effect is up to 3 months. The use of ultrasound as a guidance method is advisable.

3.1.3. Treatment of decompensation in Parkinson's disease

There are 5 factors in the development of decompensation: 1) changes in the regimen and inadequacy of antiparkinsonian therapy; 2) administration of dopamine receptor-blocking agents; 3) intercurrent illnesses (acute cerebrovascular accident, acute myocardial infarction); 4) conditions associated with the development of dehydration; 5) specific features of the disease course itself. Based on the features of the course and developmental mechanisms, 5 variants of acute decompensation can be distinguished: akinetic form (akinetic crisis) - characterized primarily by a sharp increase in hypokinesia and rigidity, leading to immobility, anarthria, and swallowing disorders; akinetic-hyperthermic form (malignant syndrome) - in addition to the manifestations of an akinetic crisis, it is characterized by hyperthermia (hyperpyrexia); dyskinetic form – characterized by severe dyskinesias, frequently accompanied by motor fluctuations and sometimes hyperthermia; psychotic (delirious) form – characterized by predominant confusion and psychotic disorders; and mixed form, characterized by a combination of various symptoms. Furthermore, in PD patients taking monoamine oxidase (type B) inhibitors when combined with antidepressants from the selective serotonin reuptake inhibitor group, one may encounter the development of serotonin syndrome.

Comments: The most significant factor in the development of acute decompensation is a change in the antiparkinsonian therapy regimen. Medications may be discontinued by the patient or physician out of a belief that they are ineffective; interruptions in medication intake during prolonged surgical interventions frequently lead to decompensation. In such cases, the patient more commonly experiences an akinetic crisis, or a malignant akinetic-hyperthermic form may develop, where in addition to a sharp increase in muscle tone and movement restriction, elevated body temperature and other autonomic manifestations will be observed. Furthermore, the drug dose may be reduced through indirect mechanisms: for example, due to impaired absorption. Therefore, in the absence of a voluntary change in the dosing regimen in decompensated patients, gastrointestinal diseases that may lead to malabsorption should be ruled out. The patient may significantly exceed the dose of dopaminergic drugs and their derivatives they are taking, which will lead to unmanageable, exhausting dyskinesias and decompensation in the form of a dyskinetic form, or its malignant variant with severe hyperthermia. All patients with acute clinical deterioration require monitoring for intercurrent diseases/conditions (infections, cardiovascular pathology, trauma, metabolic disorders) that can cause decompensation in both the motor and psychiatric spheres, leading to delirium [224].

Comments: Regardless of the cause of decompensation, maintaining respiration and hemodynamics is of paramount importance. In severe respiratory failure, intubation and mechanical ventilation are necessary. Acute renal failure may require hemodialysis. Infusion therapy aimed at correcting water-electrolyte and acid-base disorders, particularly metabolic acidosis, is crucial. Other analgesics and antipyretics and external cooling methods are used to reduce fever. Tube feeding or parenteral feeding is performed when indicated. Preventing aspiration is of utmost importance. Antibacterial therapy is indicated to prevent infections, primarily pneumonia, in immobilized patients. Concurrently, prevention of deep vein thrombosis of the lower extremities (low doses of heparin sodium**, bandaging of the lower extremities), pressure ulcers (regular repositioning in bed), and meticulous skin care are required. In patients with Parkinson's disease, the administration of propofol**, which can cause severe dyskinesia, as well as fentanyl**, morphine**, and other opioids** should be avoided whenever possible.

Comments: When discontinuing dopamine receptor agonists or other dopaminergic agents (COMT inhibitors), depending on the clinical situation, it is possible either to resume the discontinued drug or to make a compensatory increase in the dose of standard levodopa and its derivatives by 100–300 mg/day. If decompensation results from the withdrawal of levodopa and its derivatives, it should be re-prescribed at a lower dose, and then cautiously increased to the previous dose over several days if necessary. If decompensation is caused by a reduction in the dose of levodopa and its derivatives, it should be gradually increased (by 100 mg/day) until the effect is achieved. An increase in the dose of levodopa and its derivatives is also used if decompensation occurs spontaneously against the background of an unchanged treatment regimen. Given swallowing impairments, levodopa and its derivatives can be administered in dissolved form via a nasogastric tube [230–233].

Comments: Dopamine receptor blockers primarily include antipsychotics, both typical and atypical forms. In addition, it must be borne in mind that such a drug as metoclopramide**, frequently used in both internal medicine and surgery to correct gastroenterological disorders and reduce nausea and vomiting, can also cause blockade of dopaminergic receptors and the development of acute decompensation. Decompensation may develop even with the use of an atypical antipsychotic [234–240].

Comments: Despite the lack of systematic studies, amantadine** has long been used both in the treatment of Parkinson's disease and in the management of neuroleptic malignant syndrome, which is very similar in its mechanism of development to the akinetic-hyperthermic variant of decompensation. The mechanism of action of amantadine** is related to the blockade of NMDA-type glutamate receptors, which explains its effectiveness in treating PD decompensation, given the critical role of enhanced glutamate release in the development of acute decompensation. According to J. Kornhuber and M. Weller (1994), reduced activity of the dopaminergic system induces hyperactivity of glutamatergic systems, which may be associated with symptoms of acute clinical deterioration. In moderately severe decompensation, amantadine** is administered IV at a dose of 200 mg (500 ml) 2 times a day for 5–10 days. In severe decompensation, at a dose of 200 mg (500 ml) 3 times a day for 10–14 days. The effect of parenteral amantadine** develops in the first 5–10 days and then stabilizes. After discontinuing parenteral administration, switching to oral amantadine** at a dose of 300–600 mg/day is mandatory to avoid clinical deterioration [241–243].

Comments: In some cases, against the background of excessive intake of dopaminergic agents, patients develop severe, intractable, exhausting dyskinesias. Occasionally, these are accompanied by a pronounced temperature response with hyperthermia up to 40 °C and elevated creatine phosphokinase (CPK) levels. If a dyskinetic variant of decompensation develops, the dose of dopaminergic agents must be restricted, but they should not be completely discontinued. Dose reduction should be gradual, decreasing levodopa and its derivatives by 100 mg per day until stabilization is achieved [244–245].

Comments: Adamantane derivatives have a solid evidence base and have long been used as agents for correcting drug-induced dyskinesias in PD patients. In urgent conditions, preference should be given to the infusion form, which provides a faster therapeutic response. The recommended dose is 200 mg (500 ml) 2–3 times a day depending on the condition for 10–14 days, followed by a transition to oral administration of 300–600 mg per day. Given the frequent presence of cognitive and psychotic manifestations in patients with dyskinesias, caution must be exercised when administering the drug, and it should be used only when the expected benefit outweighs potential risks [246–250].

Comment: #Quetiapine** and clozapine are the most studied atypical antipsychotic agents used for psychosis in PD.

3.1.4. Treatment of cognitive impairment in Parkinson's disease

The treatment of patients with cognitive impairment (CI) in Parkinson's disease is determined by the severity of the cognitive deficit and its impact on various aspects of the patient's daily life, as well as primary and concomitant diseases. Treatment approaches differ fundamentally depending on whether the cognitive impairment reaches the stage of dementia. They include both pharmacological and non-pharmacological methods and involve the correction of not only cognitive but also other neuropsychiatric (behavioral, psychotic, affective) disturbances.

When cognitive impairments appear in patients, an assessment and, if necessary, adjustment of ongoing therapy is required: reducing the dosage or discontinuing drugs capable of exerting a negative effect on cognitive functions.

There are isolated studies indicating a potential positive effect of certain dopaminergic agents on the dynamics of cognitive impairment in Parkinson's disease patients. In particular, data exist regarding amantadine**, monoamine oxidase (type B) inhibitors such as rasagiline, and the dopamine receptor agonist piribedil** [256–260], though the existing evidence base is insufficient to draw a definitive conclusion. It should also be borne in mind that in cases of rapidly progressive CI or the development of dementia, dopaminergic agents (primarily dopamine receptor agonists) can provoke psychotic disorders in PD patients.

3.1.4.1. Treatment of mild cognitive impairment in Parkinson's disease

The management strategy for patients with mild cognitive impairment (MCI) involves two main goals: secondary prevention of MCI progression (prevention of dementia) and reduction of the severity of MCI and its impact on the patient's life. Currently, data confirming the benefits of any drug treatment in patients with MCI in Parkinson's disease are insufficient. Current studies of non-pharmacological treatments for cognitive dysfunction in PD are also very limited in quantity and quality. It is necessary to adhere to the general rules of management of patients with MCI, including the correction of modifiable risk factors, as well as non-pharmacological methods such as physical activity and cognitive training. Among the non-pharmacological methods for correcting cognitive impairment in Parkinson's disease, options for non-invasive brain stimulation using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are being considered [261]. Despite isolated data indicating a positive effect of stimulation on certain cognitive functions, additional evaluation of efficacy and safety in larger-scale studies is required [262, 263].

Comments: Cognitive impairment can be a direct consequence of the administration of drugs with sedative and anticholinergic effects, as well as beta-blockers, which emphasizes the importance of analyzing and correcting concurrent pharmacotherapy [266, 267].

Comments: Physical inactivity is one of the main risk factors for dementia. Numerous studies have shown a protective effect of combined physical exercises in elderly individuals regardless of cognitive status [270]. Clinical studies have shown that in patients with Parkinson's disease, various forms and intensity levels of exercise can improve cognitive functions, especially executive functions [271, 272]. However, the most effective forms, intensity, mechanisms, and duration of exercise have not yet been determined. Clinical trial data indicate that a more intensive aerobic exercise program, including strength and balance training, may contribute to a greater cognitive effect [273 - 276].

Comments: cognitive stimulation in patients can be carried out both through active exercises (cognitive training) and by maintaining a high level of daily, social, and professional activity. It is assumed that in patients with MCI, cognitive stimulation allows for a more intensive engagement of the cognitive reserve. A multitude of cognitive stimulation techniques have been proposed, which complicates the analysis of cumulative information and does not allow for definitive conclusions regarding the efficacy of a particular methodology [276]. According to systematic reviews, the desired effects of such an intervention outweigh the potential risks and, thus, can be recommended for all patients with MCI; however, due to the limited amount of data regarding the use of cognitive stimulation in patients with Parkinson's disease, this conclusion is conditional [280 - 283].

Comments: Cholinesterase inhibitors belong to the medications used in the treatment of various nosological forms of dementia, including Parkinson's disease. Nevertheless, in randomized controlled trials of various cholinesterase inhibitors (donepezil and rivastigmine**), it was not possible to demonstrate the effects of this therapy in MCI in terms of the timing of subsequent dementia development [284, 285]. In addition, the frequency of adverse gastrointestinal and cardiac events was significantly increased in the therapeutic groups. Combined, this does not allow recommending such therapy in the management of patients with MCI. Since the boundary between MCI syndrome and mild dementia is not always distinct, careful analysis of the specific clinical situation is required when deciding on the prescription of cholinesterase inhibitors.

3.1.4.2 Treatment of dementia in Parkinson's disease

The basis of therapy is the use of basic drugs for the treatment of dementia, which include two types of drugs — cholinesterase inhibitors (ChEIs) and memantine** (which chemically acts as a glutamate NMDA receptor antagonist). These drugs not only affect the key manifestations of cognitive impairment [286], but also contribute to improving the patient's overall functional status, the quality of life of both the patient and those around them, and have a positive effect on the severity of concomitant neuropsychiatric disorders.

Evaluation of the efficacy of anti-dementia therapy should be carried out on a regular basis at least once every 6 months or depending on changes in the patient's condition.

Comments: Cholinergic deficiency is one of the factors in the development of dementia in PD. Therefore, cholinergic therapy can be considered fundamental in the treatment of cognitive impairment in Parkinson's disease, and ChEIs are the drugs of choice. ChEIs have a significant impact on attention, information processing speed, executive functions, memory, and speech compared to placebo. Only one drug from the cholinesterase inhibitor group is officially approved for the treatment of dementia in Parkinson's disease — rivastigmine**, which is a selective inhibitor of brain acetyl- and butyrylcholinesterase with the largest evidence base [291]. Galantamine is less well studied. Clinical trials have also been conducted for other acetylcholinesterase inhibitors (donepezil and galantamine**) to evaluate their efficacy and safety in the treatment of patients with dementia in Parkinson's disease. The results of clinical studies regarding the use of donepezil are contradictory, which makes it difficult to evaluate its efficacy in the treatment of dementia in Parkinson's disease [287]. The evaluation of the efficacy and safety of galantamine** was carried out in a single open-label controlled study [290]. Nevertheless, many experts consider it possible to prescribe galantamine** for the treatment of dementia in Parkinson's disease due to its proven anti-dementia activity in other neurodegenerative diseases [290]. According to meta-analysis data, the use of rivastigmine** was marked by a greater number of adverse events compared to donepezil, in particular, increased tremor [286]. However, long-term safety data from a 76-week prospective open-label randomized study in patients with mild to moderate dementia (n = 583) showed that treatment with rivastigmine** capsules (12 mg/day) or patch (9.5 mg/24 h patch) is well tolerated [291]. No negative effect on the severity of motor disorders was noted for any of the drugs from the ChEI group [284]. Titration of cholinesterase inhibitors should be carried out gradually from starting doses until the "target" dose is reached. If the target dose effect is insufficient, it is possible to increase it to the maximum dose (Appendix A3).

Comments: Dementia associated with Parkinson's disease is not an approved indication for #memantine**, however, the efficacy and safety of #memantine** at a dose of 20 mg per day in patients have been proven by RCT results [294, 296]. #Memantine** has a significant effect on attention, processing speed, and executive functions [295]. Comparative studies of memantine versus anticholinesterase agents have not been conducted. Several studies have demonstrated a positive effect of #memantine** on the quality of life in patients with Parkinson's disease dementia [298].

3.1.5. Treatment of affective, behavioral, and psychotic disorders in Parkinson's disease

Depression therapy is carried out in three areas: correction of dopaminergic therapy, prescription of antidepressants, and the use of non-pharmacological treatment methods.

3.1.5.1. Adjustment of dopaminergic therapy in patients with motor fluctuations and depressive symptoms during the "off" period

Comments: A lowered mood is one of the characteristic manifestations of symptom fluctuations during "wearing-off" ("off" period) [302].

3.1.5.2. Adjustment of dopaminergic therapy in patients with depression not related to symptom fluctuations

Comment: The antidepressant effect of #pramipexole** at a dose of 1.5 - 3.0 mg/day was confirmed in an international multicenter double-blind placebo-controlled trial. A statistically significant reduction in manifestations of depression during therapy generally did not correlate with the antiparkinsonian action of the drug. The lack of correlation between the dynamics of motor symptoms and depression during pramipexole** administration indirectly indicates an independent antidepressant effect of the drug, not related to its antiparkinsonian action [303]. In a randomized study of pramipexole** and the antidepressant sertraline**, an antidepressant effect manifested as an improvement in scores (by 50% or more) on the Hamilton Depression Rating Scale (HDRS) was identified in 69.7% of patients receiving pramipexole** and 48.5% of those taking sertraline** [305].

Comments: A potential antidepressant effect has been demonstrated as a result of placebo-controlled studies of #ropinirole at a dose of 8 - 16 mg per day [305], and rasagiline [306]. Negative results were obtained in evaluating the antidepressant effect of therapy with other dopamine agonists [307]. No controlled studies have been conducted on the effect of levodopa preparations and their derivatives on depression. There is evidence of a reduction in depression during therapy with levodopa preparations and their derivatives in the early stages of the disease [308].

3.1.5.3. Use of antidepressants in the treatment of depression in Parkinson's disease

Comments: In randomized placebo-controlled trials in patients with PD, an antidepressant effect was demonstrated for selective serotonin reuptake inhibitors (SSRIs) — sertraline** 25 - 50 mg/day, paroxetine** 20 - 40 mg/day, citalopram 20 mg/day; other antidepressants (serotonin-norepinephrine reuptake inhibitors (SNRIs)) venlafaxine 75 - 150 mg/day [309 - 312], and non-selective monoamine reuptake inhibitors (TCA) — amitriptyline** 12.5 — 25 mg/day [313]. When prescribing SSRIs/SNRIs in the first 2 weeks of therapy, a drug with an anxiolytic effect may be prescribed (e.g., etifoxine 50 mg 3 times a day, tofisopam 50 mg 2 - 3 times a day).

SSRIs may increase tremor (in more than 5% of cases) and very rarely worsen parkinsonism. Taking into account the broader spectrum of potential adverse events of TCAs (worsening of cognitive impairment and provocation of psychotic disorders; orthostatic hypotension, cardiac rhythm disturbances, slowing of gastrointestinal motility, urinary retention). SSRIs or SNRIs are the antidepressants of first choice.

In case of insufficient effect of one of the SSRI drugs or after six weeks of therapy, it can be substituted with an SNRI. In case of ineffectiveness of the SNRI, the administration of a TCA may be considered with monitoring of the adverse events mentioned above. The duration of therapy should be at least 6 months [314] (Appendix B).

Comments: In cases where depression and insomnia are combined, sedative antidepressants may be recommended (#trazodone 50 - 150 mg/day, #mirtazapine 7.5 - 30 mg/day, agomelatine** 25 - 50 mg ) [72, 314, 747].

3.1.5.4. Non-pharmacological therapy for depression in Parkinson's disease

Alongside the adjustment of pharmacotherapy, all patients require psychological support, which should primarily include elements of rational psychotherapy explaining the potential curability of most disease symptoms and modern treatment options. Additionally, educational programs for patients and caregivers, and social support in the form of involvement in PD patient associations can be utilized.

Comments: A number of studies in patients with PD have noted an improvement in standardized depression ratings following rTMS [317 - 318]. The antidepressant effect of these methods is considered possible and requires further clarification. The short-term effect of rTMS and the need for its regular repetition should be taken into account.

3.1.5.4. Therapy for apathy in Parkinson's disease

According to observational studies, apathy is observed in 13 - 60% of patients with PD. It is considered an independent motivational deficit syndrome in PD, and in some cases may be a symptom of depression. The main manifestations of apathy include reduced motivation with a limitation of goal-directed behavior, cognitive activity, and emotional responses.

Comments: In a meta-analysis of randomized controlled trial results for pramipexole**, 63.2% of 70 patients with apathy receiving the drug therapy experienced a reduction in apathy compared to 45% of patients receiving placebo [321]. The efficacy of dopamine agonists for apathy has been demonstrated when prescribing piribedil** to patients with PD and apathy developing after deep brain stimulation of the subthalamic nucleus [322].

Comments: A reduction in apathy in patients with PD and dementia was demonstrated in a placebo-controlled study of rivastigmine** [323].

In cases of coexisting apathy and depression, prescribing an antidepressant may be effective. To correct apathy, it is important to use a complex of non-pharmacological methods—CBT and rehabilitation aimed at increasing the cognitive, motor, and social activity of patients. However, experience with these methods, as well as other types of non-pharmacological interventions (music therapy, light therapy, activation therapy, multisensory therapy), is currently insufficient.

3.1.5.4. Management of fatigue in Parkinson's disease

Fatigue, which occurs in on average 40 - 60% of patients with PD, is defined as a feeling of almost constant tiredness, lack of energy, and physical and/or mental exhaustion.

Comments: In case of insufficient correction of motor disorders, it is advisable to adjust the doses of dopaminergic drugs and/or dopamine receptor agonists (DRAs). If rasagiline is prescribed in patients with adequately corrected motor disorders, a reduction in the dose of dopaminergic drugs and/or DRAs may be required. Considering the likely heterogeneity of fatigue, if depression, nocturnal sleep disorders, or cognitive decline are diagnosed, the dynamics of fatigue should be assessed after correcting these disorders [325]. The efficacy of physical therapy methods for fatigue is currently being investigated [326].

3.1.6. Treatment of sleep-wake disorders in Parkinson's disease

The prevalence of sleep disorders in patients with Parkinson's disease (PD) ranges from 60 to 98%. The most frequent and significant disorder impairing daily activities in PD patients is insomnia. The leading manifestations of insomnia in PD patients are difficulty falling asleep and frequent awakenings (sleep fragmentation), and less commonly, early awakenings leading to reduced sleep duration and efficiency.

3.1.6.1. Treatment of insomnia

The treatment of insomnia in PD patients requires clarifying the likely causes of sleep-onset and sleep-maintenance difficulties, such as motor symptoms of PD, affective disorders, or psychotic symptoms. The main components include optimizing dopaminergic therapy, correcting circadian rhythm disorders, adhering to sleep hygiene, prescribing melatonin, and treating non-motor symptoms of PD that disrupt sleep (depression, anxiety, hallucinations, pain, neurogenic bladder, nocturnal apneas).

Comments: Small placebo-controlled studies have demonstrated an increase in sleep duration and an improvement in nocturnal sleep quality accompanied by a reduction in nocturnal hypokinesia when using a bedtime dose of standard levodopa preparations [331], the DRAs pramipexole** [332], ropinirole [333], or other DRAs [334]; however, improvement in nocturnal sleep was not confirmed with the administration of piribedil** [335]. In patients with the "wearing-off" phenomenon who experience nocturnal awakenings due to worsening nocturnal hypokinesia and muscle rigidity 2 - 4 hours after falling asleep, and/or early morning awakenings due to morning hypokinesia and dystonic spasms (cramps), the bedtime dose of a standard levodopa preparation may be replaced with a combined formulation of levodopa + entacapone + [carbidopa] [336 - 339].

Thus, when selecting the nighttime dose of dopaminergic drugs or DRAs for the correction of motor symptoms, it is necessary to carefully evaluate the dynamics of nocturnal symptoms in order to prescribe the minimum effective dose of dopaminergic agents. Limitations for prescribing DRAs include their potential adverse effects, such as hallucinations and episodes of nocturnal confusion. It is advisable not to prescribe DRAs to patients with severe cognitive impairment or dementia, as they carry a high risk of provoking psychotic disorders. Insomnia is a potential adverse effect of amantadine**; therefore, the drug should be taken in the first half of the day.

Comments: Improvement in the subjective assessment of nocturnal sleep quality, manifested as a decreased sleep-onset latency and a reduction in the number and duration of nocturnal awakenings following the administration of 3 - 6 mg of melatonin at bedtime, has been demonstrated in several small controlled studies. Melatonin may be recommended as a primary treatment for sleep disorders provided that secondary causes of insomnia (motor, sensory, affective, and behavioral disorders) are corrected.

Comments: Improvement in sleep quality, decreased sleep-onset latency, and reduction of nocturnal awakenings in PD patients have been demonstrated with zaleplon 5 - 10 mg, zopiclone 7.5 mg, and zolpidem 10 mg. In elderly patients, half-doses are prescribed [341, 342, 343].

Comments: To correct insomnia caused by depression and anxiety, other sedating antidepressants are prescribed (#trazodone 50–150 mg per day, #mianserin 15–30 mg/day). However, the potential for worsening RLS or RBD during their administration should be considered [342, 343, 747].

For sleep disturbances due to psychotic symptoms, atypical antipsychotics may be used: #clozapine 12.5–25 mg, #quetiapine** 25–50 mg at bedtime [342, 343, 747, 748].

For nocturia caused by overactive bladder (frequent nighttime urges to urinate with no residual urine (not exceeding 50 ml) according to ultrasound data), anticholinergic agents may be used. It is necessary to keep in mind the possibility of the onset or worsening of cognitive and psychotic impairments when taking drugs of this group.

Comments: Cognitive behavioral therapy (CBT) for insomnia is recommended as the first-line treatment for chronic insomnia in the general population [342]. In patients with PD, the efficacy of CBT has been demonstrated in a number of small studies [344].

Improvement in sleep quality has been demonstrated in patients with PD against the background of increased physical activity [345]. The efficacy of light therapy for sleep disorders in patients with PD has been noted [346].

Sleep normalization is promoted by adherence to sleep hygiene rules: limiting daytime sleep (especially in the afternoon); optimal physical activity during the day; creating optimal sleep conditions (sleeping in a dark, quiet, well-ventilated room); patients are taught to associate the bedroom only with sleep and sex, to avoid unpleasant thoughts or attempts to mentally solve domestic or professional issues in bed; getting out of bed at the same time in the morning; going to bed when feeling sleepy; if unable to fall asleep within 20 minutes, getting up and engaging in a quiet activity, and then going back to bed when sleepiness appears; limiting activating activities before bed (watching TV, physical exercises), reducing emotional and mental load in the evening; avoiding strong tea, coffee, and heavy meals at night. Physical activity during the day, but no later than 3 hours before bedtime, contributes to sleep normalization; a useful practice is a bedtime routine—an invariable set of actions in terms of time and sequence preceding sleep.

3.1.6.2. Treatment of parasomnia - rapid eye movement (REM) sleep behavior disorder (RBD)

Comments: The efficacy of melatonin and #clonazepam** in RBD has been demonstrated in the general population. In PD, the efficacy of therapy has been investigated in isolated controlled studies. When prescribing #clonazepam**, the benefit/risk ratio of therapy should be weighed, taking into account potential cognitive decline, worsening of postural instability, and development of tolerance. One should keep in mind the possible worsening of RBD upon increasing the dose of dopaminergic agents, or prescribing SSRIs and other antidepressants (SNRIs).

3.1.6.3. Treatment of Daytime Sleepiness and Unexpected Daytime Sleep Attacks

Daytime sleepiness (DS) in PD manifests as a sensation of sleepiness during the day (in an average of 40–50% of patients) and/or short involuntary sleep attacks (SA) in 10–15% of patients. DS may be caused by other PD symptoms or represent an independent manifestation of the disease. Management of DS is important due to the potential life-threatening risk when driving and the increased risk of trauma in everyday life.

Considering the multifactorial nature of DS, an analysis of its potential secondary causes is necessary: nocturnal sleep disorders, changes in dopaminergic therapy (prescribing dopamine receptor agonists [DRAs]), presence of depression, dementia, apathy, autonomic disorders (postprandial hypotension), and use of medications with sedative effects.

Comments: The risk of DS increases with a higher cumulative dose of dopaminergic agents. A greater risk of DS is associated with the use of DRAs (compared to levodopa and its derivatives) [350]. Therefore, discontinuing or reducing the dose of DRAs, switching DRAs to rasagiline or amantadine**, as well as reducing the dose of levodopa and its derivatives when possible, can reduce DS. If sleepiness occurs at the initial stage of treatment with DRAs or levodopa and its derivatives, it may be possible to reduce DS by using a slower dose titration schedule.

Comments: A reduction in sleepiness following the correction of nocturnal sleep disorders has been demonstrated in PD patients with obstructive sleep apnea receiving CPAP therapy [351].

3.1.7. Treatment of psychotic symptoms in Parkinson's disease

The main components of therapy for psychotic disorders include the correction of triggering factors, optimization of antiparkinsonian therapy, and the administration of antipsychotic agents.

Comments: The identification and correction of triggering factors are relevant when psychotic disorders of any severity manifest, especially during the development of delirium. Delirium therapy can be carried out in an intensive care unit or, if necessary, in a psychosomatic department. Measures are required to prevent somatic disorders that cause delirium: optimal hydration, adequate nutrition; for immobilized patients, the use of antibiotics and low doses of unfractionated heparin**, etc.

Comments: The adjustment of the dopaminergic drug regimen should be carried out by the gradual withdrawal of antiparkinsonian drugs, taking into account their psychotogenic potential. Drugs are usually withdrawn from the regimen in the following order: anticholinergics (tertiary amines) – adamantane derivatives – DRAs or monoamine oxidase (type B) inhibitors – other dopaminergic drugs (COMT inhibitors). After withdrawing each drug, the effect on both psychotic symptoms and motor functions should be assessed. In the case of a clinically significant worsening of motor functions, the dose of levodopa and its derivatives is increased. In cases of visual hallucinations against the background of preserved insight, adjusting the dopaminergic drug regimen is a sufficiently effective therapeutic approach.

Comments: Despite the relatively low risk of aggravated parkinsonism during treatment with atypical antipsychotics, they should be used at the minimum effective doses, and long-term use of these drugs should be avoided whenever possible. Clozapine has greater efficacy from an evidence-based medicine standpoint than quetiapine**. However, taking into account the even low risk of agranulocytosis associated with clozapine (in 1% of cases), which requires blood count monitoring, therapy with quetiapine** is considered safer.

Comments: A reduction in hallucinations in patients with PD and dementia has been demonstrated in small controlled studies of #rivastigmine** and #donepezil. The use of cholinesterase inhibitors can be considered not only as symptomatic but also as pathogenetic therapy for psychotic disorders (similar to cognitive impairment).

3.1.8. Treatment of behavioral disorders in Parkinson's disease

The main components of therapy for behavioral and psychotic disorders are the adjustment of dopaminergic therapy, CBT, treatment of concomitant affective disorders, and the administration of antipsychotic therapy.

Comments: The evidence base for the treatment of behavioral disorders is currently insufficient. The main recommendations are provided based on data from limited studies and the principles of "good clinical practice".

3.1.9. Treatment of autonomic dysfunction in Parkinson's disease

Main directions of therapy: correction of cardiovascular, gastrointestinal, and urogenital disorders.

3.1.9.1. Treatment of orthostatic hypotension

Orthostatic hypotension (OH) is a drop in systolic blood pressure of more than 20 mm Hg and/or diastolic blood pressure of more than 10 mm Hg within 3 minutes of standing up from a lying position [361, 362]. Clinically, it manifests as symptoms of orthostatic dizziness, lightheadedness, blurred vision or darkening before the eyes, unsteadiness, general weakness, and syncopal episodes. The goal of OH therapy is to improve the patient's functional capabilities and quality of life, and to prevent syncope, falls, injuries, and other complications. OH in PD can be exacerbated by cardiovascular and other somatic diseases, as well as the intake of certain medications. All cases of severe OH and other cardiovascular disorders in PD require follow-up by a general practitioner/internist. Pharmacotherapy for OH is usually required if OH is clinically significant and impairs daily activities [363, 364].

The management strategy for orthostatic hypotension (OH) includes several sequential stages [360, 363, 364, 366]:

1. assessment and review of blood pressure-lowering medications, including agents used to treat urological disorders and Parkinson's disease (PD), with the aim of discontinuation or dose reduction (must be discussed with the prescribing physician);
2. patient and caregiver education on strategies to avoid factors that trigger blood pressure drops and non-pharmacological methods for managing OH (Appendix B) [367 - 372];
3. pharmacotherapy.

In the event of frequent syncope and falls, necessary emergency measures to stabilize the condition [361, 365].

Comments: Factors provoking OH and strategies for avoiding them are detailed in Appendix A3.

Comments: Increasing salt intake is only possible in patients without supine hypertension, risk of heart failure, or pronounced peripheral edema.

Comments: A single intake of 500 ml of water helps to immediately increase blood pressure by 5 - 10 mm Hg in case of its sharp drop in a patient with PD [381 - 384].

Comments: Fludrocortisone** enhances renal sodium reabsorption and potassium excretion, increases blood volume and cardiac output. The drug is considered effective for OH in patients with PD [365, 387]. The most complete therapeutic effect is achieved by combining the drug with a high-salt diet (8 g per day), adequate fluid intake (2 – 2.5 liters per day), and elevating the head of the bed by 20 - 30 cm [373]. However, special attention should be paid to the numerous side effects of the drug: arterial hypertension (especially in the supine position), cardiac arrhythmias, electrolyte imbalance (hypokalemia), edema (mostly of the legs, but pulmonary edema is possible), and others. To prevent hypokalemia, potassium-rich foods (fruits, vegetables, poultry, fish, and meat) are recommended [361]. In case of supine hypertension, the use of calcium channel blockers (e.g., nifedipine**) at bedtime may be considered [361, 363].

In cases of OH worsening during dopaminergic therapy, domperidone (a gastrointestinal motility stimulant) is advisable; clinical trials have shown its positive effect on OH in patients with PD [387, 388].

3.1.9.2. Treatment of sialorrhea in PD

Sialorrhea in PD may be related to hypersalivation as well as swallowing impairment [389, 390], which increases the risk of aspiration, pneumonia, oral and skin infections; daytime sialorrhea impairs social adaptation [391, 392].

Therapeutic methods for sialorrhea in PD are currently under active development but lack sufficient evidence levels; the most effective method for reducing sialorrhea is the use of botulinum toxin type A** [392].

As a non-pharmacological method to stimulate swallowing movements and saliva clearance, patients with PD and sialorrhea can be recommended to use chewing gum or hard candies [393, 394].

It should be taken into account that a number of drugs used to treat PD can increase salivation: anticholinesterase agents, quetiapine**, clozapine [395, 396], and they should be discontinued or their dose reduced if possible [396].

Correction of dopaminergic therapy can improve swallowing and reduce sialorrhea [397].

Comments: Patients with pronounced sialorrhea in PD may receive injections of #botulinum toxin type A**. The drug blocks the presynaptic release of acetylcholine in parasympathetic ganglia. The efficacy of the drug in patients with PD with sialorrhea has been demonstrated in systematic reviews using 12 [398] and then 21 [399] clinical trials, as well as via meta-analysis of several randomized controlled trials [400]. However, today the methodology and guidelines for injection sites and doses of the drug are still under development [498]. Reviews report the advantage of bilateral injections into the parotid or submandibular salivary glands; effective doses range from 100 to 250 units, and the effect of the drug persists for up to 3 months. Ultrasound guidance is preferred. Side effects are mild and transient, including dry mouth, changes in saliva composition, and mild swallowing difficulties.

Anticholinergic agents can reduce sialorrhea, but caution should be exercised due to worsening of cognitive function, urination, increased constipation, and induction of drowsiness [401].

3.1.9.3. Treatment of gastric motility disorders in PD

The phenomenon of slow and incomplete gastric emptying can be asymptomatic or cause nausea, vomiting, bloating, early satiety, postprandial fullness, and pain. Impaired gastric motility affects food assimilation, leads to malnutrition, hinders the absorption of drugs, including dopaminergic ones, worsens parkinsonian motor symptoms, and reduces patients' quality of life. The goal of treating gastric motility disorders in PD is to relieve symptoms, correct nutritional deficiency, and improve gastric emptying [402]. Non-pharmacological therapies for gastric motility disorders are poorly studied. It is advisable to advise patients on light physical exercise and dietary modifications: eating smaller meals more frequently, and using soft or liquid foods [403].

Comments: Domperidone accelerates gastric emptying and reduces dopaminergic gastrointestinal symptoms (blocks the peripheral effects of dopamine and its derivatives, stimulates GI motility), prescribed at 10 mg 20 - 30 minutes before meals 3 times a day

Comments: Metoclopramide** is a dopamine receptor blocker with peripheral and central effects, through which it can worsen parkinsonian motor symptoms and dyskinesia, and increase hypotension, especially in patients with peripheral autonomic failure [406].

3.1.9.4. Treatment of constipation in PD

Constipation (fewer than three bowel movements per week and straining during defecation) significantly reduces patients' quality of life, leads to impaired absorption of drugs including dopamine and its derivatives, malnutrition, and weight loss. The occurrence of constipation in PD besides autonomic dysfunction is caused by factors such as the use of certain medications (especially anticholinergics and opioids), low physical activity, and inadequate fluid intake; correction of these factors must be included in the treatment regimen. Constipation treatment should be staged, starting with non-pharmacological methods and then, if ineffective, pharmacotherapy [407]:

1) lifestyle changes and dietary modifications, use of dietary fiber supplements;

2) where possible, minimization or discontinuation of medications that exacerbate constipation;

3) use of osmotic laxatives;

4) use of stimulant laxatives.

The algorithm for treating constipation in PD is presented in Appendix B [407, 408].

Comments: It is advisable to increase fluid intake up to 2 L/day and include foods rich in dietary fiber (vegetables, fruits) in the diet. Dietary fiber supplements, such as bran, are effective (if there are no swallowing difficulties) between meals, washed down with 2 glasses of water [365]. Fiber supplements must be accompanied by a large amount of water; otherwise, constipation may worsen. The prescription of dairy products with probiotics containing bifidobacteria and prebiotics containing fructooligosaccharides can be useful [409]. Patients should also be advised to follow a routine, i.e., eat meals at the same time.

Comments: Physical exercise and abdominal massage are beneficial. In severe cases, enemas and manual evacuation techniques may be required [365].

Comments: Macrogol** increases the osmotic pressure and volume of fluid contained in the intestine, enhancing peristalsis. The efficacy of the drug was demonstrated in a randomized placebo-controlled clinical trial in patients with PD: there was an increase in stool frequency, a decrease in straining during defecation, normalization of stool consistency, and discontinuation of rectal laxatives. Adverse events included mild bloating, nausea, and occasionally diarrhea [410].

Comments: Lubiprostone enhances fluid secretion into the intestinal lumen, facilitates the passage of intestinal contents or fecal masses, leading to an increased frequency of bowel movements, disappearance of bloating and abdominal discomfort, normalization of fecal consistency, and a reduction in straining time. The drug does not affect electrolyte balance and does not cause dehydration with prolonged use. In a randomized placebo-controlled clinical trial in patients with constipation and PD, lubiprostone showed significant efficacy at a dose of 24 mcg twice daily; adverse events were mild, with episodic diarrhea being the most common [411].

Comments: Lactulose** exerts a hyperosmotic laxative effect, softens stools, stimulates intestinal peristalsis (acts only in the colon), and normalizes microflora as a prebiotic agent.

Stimulant contact laxatives, such as bisacodyl** (in tablets or rectal suppositories), sennosides A and B**, and sodium picosulfate, may be prescribed for a short time for severe constipation in patients with PD, provided that osmotic laxatives are ineffective [412, 365]. Daily prolonged intake of high doses of these drugs is undesirable, as it can lead to fluid loss, electrolyte imbalance, and hypokalemia.

Prucalopride is a selective, high-affinity 5-HT₄ serotonin receptor agonist, which most likely explains its effect on intestinal motility; it is believed that it may be effective in patients with constipation in PD [412].

Comments: Drugs with anticholinergic activity (anticholinergics, tricyclic antidepressants, opioids) can worsen constipation; some of these drugs are frequently used in PD and should be discontinued if possible if constipation occurs [412].

3.1.9.5. Treatment of overactive bladder syndrome in PD

Overactive bladder is accompanied by frequent urination, urgency sometimes with urinary incontinence, and nocturia, which can significantly impair patients' quality of life and require correction. Overactive bladder syndrome in PD develops due to autonomic regulation disorders. However, before initiating therapy, other possible causes of irritative symptoms must be excluded: pelvic floor muscle weakness, history of surgical interventions, use of certain medications, and urogenital infections. All patients with urological pathology require a consultation with a urologist and a collegial choice of treatment tactics. Non-pharmacological interventions for overactive bladder in patients with PD aim at behavioral and lifestyle modifications and currently lack a strong evidence base. Pharmacological therapy includes adjusting dopaminergic medications (towards increasing their effect), prescribing anticholinergics, and medications for frequent urination and urinary incontinence [413, 365].

In the presence of irritative symptoms in patients with PD, pelvic floor muscle training, timed voiding, and exclusion of caffeine and alcohol from the diet are advisable [414]. Restricting fluid intake at least 4 hours before bedtime [414], sleeping with the head of the bed elevated by 15–20°, and using a bedside urinal at night can help patients with nocturia [365, 414].

In patients with PD (especially those who have not previously received dopaminergic therapy), adequate selection of dopaminergic agents (levodopa + benserazide**, levodopa + carbidopa**) can reduce urination disorders [415–417], and optimization of nighttime dopaminergic therapy can help patients suffering from nocturia [365, 418–422].

Comments: #Desmopressin metered nasal spray (a synthetic analog of the antidiuretic hormone) has demonstrated efficacy in treating nocturia in patients with PD in a number of clinical trials [365, 421–425]. Caution is required when prescribing it due to the potential development of hyponatremia, especially in patients over 65 years of age [414].

Comments: Solifenacin** is a specific competitive inhibitor of muscarinic receptors, predominantly of the M₃ subtype; nevertheless, the drug should be used with caution in elderly patients due to the risk of cognitive decline [427]. Other anticholinergic drugs, such as trospium chloride and darifenacin (which have a low ability to penetrate the central nervous system, thereby reducing the risk of central side effects), as well as tolterodine and oxybutynin, can be used to treat overactive bladder in patients with PD, although they have a lower level of evidence [365]. Frequent side effects of such therapy in patients with PD include dry mouth, dyspepsia, and constipation; furthermore, vigilance is required regarding cognitive decline and the emergence of obstructive urological symptoms [414].

Comments: Tolterodine may be used for the treatment of overactive bladder in patients with PD

Comments: Mirabegron improves bladder storage function by stimulating β₃-adrenoceptors in its walls. In a meta-analysis of clinical trials, mirabegron demonstrated better tolerability regarding dry mouth compared to solifenacin**, while their efficacy was similar [428]. Nevertheless, adverse events are possible, including hypertension, cardiac rhythm disorders, and abdominal or pelvic pain [429].

Comments: Administration of #botulinum toxin type A** into the detrusor muscle can improve urodynamics for several months in patients with PD with overactive bladder. The effective dose is 100 units (maximum 300 units) [430–432, 753].

Clinical trials show that deep brain stimulation (subthalamic nucleus DBS) can have a positive effect on detrusor overactivity in patients with PD [433, 434]. Percutaneous tibial nerve stimulation may help patients with PD suffering from overactive bladder if medical treatment is contraindicated [435].

3.1.9.6. Treatment of bladder emptying disorders in PD

Bladder underactivity presents with obstructive symptoms such as prolonged micturition time, straining during urination, intermittent and weak stream, feeling of incomplete bladder emptying, and urinary retention. Bladder underactivity is much less common in Parkinson's disease than overactivity. To clarify the nature of the disorders, it is recommended to perform an ultrasound examination of the bladder with determination of residual urine volume (a volume of more than 100 mL indicates detrusor hyporeflexia) and a urodynamic study with electromyography. Usually, the symptoms are caused by obstructive uropathy (usually due to prostate adenoma in men, bladder neck stenosis in women); otherwise, it is necessary to perform a differential diagnosis with multiple system atrophy and to exclude the influence of anticholinergic drugs [418]. Patients with obstructive symptoms require discontinuation of anticholinergic agents (tertiary amines) before starting any treatment. Therapy for patients with Parkinson's disease has not been established; treatment is carried out by a urologist in accordance with generally accepted guidelines for the treatment of underactive bladder [365].

3.1.9.7. Treatment of sexual dysfunction in PD

Patients with Parkinson's disease may experience erectile and/or ejaculatory dysfunction in men, decreased libido, orgasm disorders, and vaginal dryness in women [436]. In Parkinson's disease, these symptoms are usually multifactorial in nature, including, besides autonomic disorders, concomitant somatic diseases, depressive and motor disorders, which need correction [437]. The therapy of sexual disorders in Parkinson's disease currently has a low evidentiary base [437].

It is advisable to advise patients on lifestyle modification (smoking cessation, adequate nutrition, physical activity, sleep normalization) and consultation with a psychotherapist. Correction of depression and anxiety, optimization of dopaminergic therapy, and withdrawal of drugs that provoke erectile dysfunction or anorgasmia (selective serotonin reuptake inhibitors, β-blockers) are necessary. If non-pharmacological measures are ineffective, pharmacotherapy should be prescribed if necessary. Sometimes the addition of dopamine receptor agonists can improve sexual function in patients with Parkinson's disease [365].

Comments: Sildenafil has demonstrated efficacy in sexual dysfunction in patients with Parkinson's disease in a number of clinical trials [437 - 439]; however, patients should be warned that taking the drug does not lead to an immediate erection, does not cause it without sexual stimulation, and may sometimes fail [439]. Caution should be exercised when using sildenafil due to the risk of worsening orthostatic hypotension and the occurrence of other mild (headache, blurred vision) and severe (hypotension, priapism, cardiac arrest) adverse events [365]. Before prescribing sildenafil, it is recommended to perform an orthostatic test and notify the patient of the need for medical consultation if orthostatic symptoms appear after taking the drug [436]. Alternatively, another phosphodiesterase-5 inhibitor, tadalafil, can be used with the same precautions [436].

3.1.10. Treatment of secondary parkinsonism

3.1.10.1 Treatment of drug-induced parkinsonism

Comments: Following drug withdrawal, parkinsonism symptoms typically regress within several weeks (in most cases up to 4 months). However, in a small proportion of patients (more frequently in the elderly), recovery is slower, and symptoms may persist for a year or even longer. Slower symptom regression is also observed with long-acting preparations [442, 443].

Comments: The drugs of choice are anticholinergic agents (trihexyphenidyl** and biperiden**) or amantadine**. No clinically significant difference in efficacy and safety has been identified among existing anticholinergic agents. Anticholinergic agents should be used with caution in elderly patients due to the potential occurrence of side effects (constipation, urinary retention, memory impairment, and delirium). Cholinolytics should not be used to treat patients with concomitant tardive dyskinesia due to the risk of its worsening.

Comparable efficacy of amantadine** and anticholinergic agents has been demonstrated in several controlled studies. The higher safety profile of amantadine derivatives in this age category makes it the preferred choice for this age group.

Amantadine** can be administered both orally and intravenously by infusion. Infusion administration is indicated in the most severe cases, especially in the presence of swallowing disorders.

If monotherapy is insufficiently effective, a combination of amantadine** and an anticholinergic agent is used. Once the effect is achieved, the doses of amantadine** and the anticholinergic agent are gradually reduced over 2 - 3 months until complete discontinuation. If the patient continues to take an antipsychotic agent and is free of parkinsonism symptoms after 4 months, an attempt can be made to gradually discontinue the anticholinergic agent. If parkinsonism symptoms reappear upon discontinuation of the anticholinergic agent, long-term administration of the anticholinergic agent should be continued.

Dopamine agonists and levodopa preparations and their derivatives are not recommended in neuroleptic parkinsonism due to the possibility of worsening the symptoms of the psychiatric illness for which the antipsychotic agent was prescribed. At the same time, they can be prescribed for a short period if the patient does not suffer from a psychiatric illness and took the antipsychotic agent as an antiemetic drug, and its discontinuation did not lead to a rapid regression of symptoms.

Since, unlike antipsychotic agents, metoclopramide** is in most cases prescribed to individuals without mental disorders, not only anticholinergic agents and amantadine**, but also levodopa preparations and their derivatives are used to alleviate symptoms until functional recovery. In parkinsonism caused by agents that deplete dopamine stores in presynaptic terminals, the use of levodopa preparations and their derivatives is also possible.

Comments: In some patients, symptoms continue to progress even after discontinuation of the antipsychotic agent. This clinical course is most frequently observed when symptoms are asymmetric from the outset, similarly to Parkinson's disease. It should be hypothesized that in these patients, medications contributed to the manifestation of a degenerative process in the basal ganglia that had previously remained subclinical. However, the possibility of so-called "late parkinsonism"—an analogue of tardive dyskinesia resulting from irreversible damage (induced by neuroleptics) to substantia nigra neurons—cannot be excluded. In individual patients, signs of Parkinson's disease or another neurodegenerative disease develop months or years after the regression of drug-induced parkinsonism. Presumably, in such cases, drug-induced parkinsonism developed against the background of an early stage of a latent degenerative process that increased susceptibility to the adverse effects of antipsychotic agents [446 - 448].

3.1.10.2 Treatment of vascular parkinsonism

The treatment of vascular parkinsonism includes:

- basic therapy aimed at preventing further brain damage, which should include the correction of major vascular risk factors (primarily arterial hypertension) and be carried out taking into account the leading mechanism of brain damage (microangiopathy, cerebral atherosclerosis, cardioembolism),

- symptomatic therapy aimed at correcting parkinsonism, concomitant motor and non-motor disorders,

- rehabilitation, including training of motor functions (primarily gait, postural stability, freezing, articulation), as well as cognitive functions.

Comments: In accordance with the guidelines for the treatment of cerebrovascular diseases, in patients who have suffered a clinical episode of ischemic stroke or an ischemic episode of another localization, long-term use of antiplatelet agents, except heparin (acetylsalicylic acid** 50 - 100 mg/day, or clopidogrel** 75 mg/day), is indicated for the prevention of recurrent ischemic episodes. The administration of antiplatelet agents, other than heparin, is also possible in the progressive course of vascular brain damage without clinical episodes of stroke, if it is confirmed by clinical and neuroimaging data. In atrial fibrillation, antithrombotic agents are prescribed. In case of another risk of cardiogenic embolism or ineffectiveness of antiplatelet agents other than heparin, the administration of antithrombotic agents (warfarin**, dabigatran etexilate**, etc.) is also possible [449]. In the presence of extensive leukoaraiosis and microhemorrhages on MRI, the use of high doses of antiplatelet agents other than heparin and antithrombotic agents is associated with a high risk of hemorrhage.

When prescribing antihypertensive agents, it is important to avoid an excessive decrease in blood pressure, especially in elderly patients with extensive white matter lesions or bilateral stenosis of the main head arteries. Correction of hyperlipidemia helps to slow down the development of atherosclerotic stenosis of major cerebral arteries, reduces blood viscosity (which is especially important in diffuse lesions of small cerebral arteries), prevents the progression of coronary artery disease and, possibly, improves endothelial function, prevents inflammatory changes and amyloid deposition in the brain parenchyma [450].

When homocysteine levels are high, the administration of folic acid** (2 - 3 mg/day), pyridoxine** (20 - 30 mg/day) and cyanocobalamin** (200 mcg/day) is indicated, but controlled studies have not yet been able to prove the ability of this measure to prevent new cerebrovascular episodes or the progression of neurological deficit. Adequate correction of concomitant somatic pathology, in particular heart and respiratory failure, hypothyroidism, etc., is necessary.

The neurovascular unit can be considered as one of the most promising targets for therapeutic intervention in dyscirculatory encephalopathy. Currently, it has been shown that HMG-CoA reductase inhibitors, selective calcium antagonists with a predominantly vascular effect, ACE inhibitors, and certain phosphodiesterase inhibitors are able to increase the reactivity of small vessels and improve cerebral perfusion, but whether this effect has clinical significance remains unclear. Improvement of blood circulation in the cerebral microvasculature can also be provided by measures aimed at reducing blood viscosity (for example, smoking cessation) and improving venous outflow. Nevertheless, it is unknown whether these approaches are able to prevent the progression of motor and cognitive impairments [468].

Comments: Symptomatic therapy consists primarily in the use of antiparkinsonian drugs. The drug of first choice is dopa and its derivatives. A trial of dopa and its derivatives should be administered to all patients with PS. If well tolerated, the dose of dopa and its derivatives should be gradually increased to 1000 - 1500 mg/day.

For a long time, it was believed that dopa and its derivatives were ineffective in vascular parkinsonism, and primary resistance to it was one of the important diagnostic arguments in favor of vascular parkinsonism. Nevertheless, a positive effect of dopa and its derivatives is noted in 20 - 40% of patients (including patients with a pathomorphologically confirmed diagnosis). Moreover, with long-term therapy with dopa and its derivatives, at least a minimal positive effect is observed in almost half of the cases. The total duration of trial therapy should be at least 3 months. Only under these conditions can a conclusion be made about the previous ineffectiveness of dopaminergic agents. Nevertheless, even with the effectiveness of dopa and its derivatives, the assessment of motor impairments in vascular parkinsonism decreases by an average of 19%, whereas in Parkinson's disease - by more than 50%). In addition, the effect of dopa and its derivatives, as a rule, is not as stable as in Parkinson's disease, and rarely persists for more than 1 - 2 years.

A response to dopa preparations and their derivatives is possible in case of damage to the nigrostriatal pathways and is more often observed in lacunar lesions of the midbrain and putamen than in diffuse lesions of the periventricular white matter (according to MRI data).

Comments: In accordance with the guidelines for the treatment of vascular cognitive impairment, cholinesterase inhibitors and memantine** at a dose limited by tolerability can be used to correct cognitive impairments detected in patients with vascular parkinsonism.

The treatment of cognitive impairments in vascular parkinsonism is poorly developed and, in general, can be regarded as ineffective. Nevertheless, cholinesterase inhibitors and memantine** can attenuate the degree of dysregulatory defect in some patients, although they have a lesser effect on the level of daily activity than in patients with Alzheimer's disease.

Comments: The drugs of choice in the treatment of anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) or other antidepressants (SNRIs), while taking into account the relative resistance of vascular depression to antidepressants and the ability of other SNRI antidepressants (e.g., venlafaxine) to increase blood pressure [454]. Correction of affective disorders, primarily anxiety and depression, which have a negative impact on the subjective condition of patients and quality of life, as well as exacerbate the disabling effect of neurological deficit, may be of great importance.

Comments: More detailed recommendations are not possible due to the limited evidence base.

Comments: The effectiveness of stereotactic interventions has not been systematically studied, but as limited experience with stereotactic interventions in multisystem degenerations shows, in extranigral (not associated with substantia nigra damage) forms of parkinsonism and especially in multifocal brain damage, stereotactic operations developed to date generally prove to be ineffective [454].

3.1.11. Treatment of parkinsonism in multisystem degenerations

The treatment of various manifestations in multisystem degenerations and secondary parkinsonism has not been sufficiently studied. What they have in common is that to reduce the severity of motor symptoms, it is recommended to use only dopa preparations and their derivatives. However, unlike Parkinson's disease, in progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), the administration of dopaminergic agents should be carried out more cautiously due to the higher risk of side effects with a lower expected benefit. In addition, in multisystem degenerations, motor symptoms are combined with non-motor manifestations from the very onset of the disease, which affect the course of the disease, determine the specifics of selecting antiparkinsonian drugs, and necessitate symptomatic therapy.

Comments: Despite the fact that the lack of response to levodopa and its derivatives is one of the criteria for progressive supranuclear palsy (PSP), a positive response to levodopa and its derivatives at a dose of 1500 mg daily is observed in 25–38% of patients. The clinical response varies depending on the PSP phenotype and is maximal in the parkinsonian subtype with mild to moderate motor deficit manifestations. However, there are no definitive recommendations regarding the dose, frequency of administration, and duration of therapy—everything is determined by the attending physician based on tolerability, side effects, and the observed clinical effect [455].

Comments: Single placebo-controlled studies have failed to provide convincing evidence of the clinical efficacy of rasagiline in multiple system atrophy (MSA) and PSP [456, 457].

Comments: In PSP, there is a significant decrease in the activity of cholinergic systems, which correlates with both motor and non-motor manifestations of the disease. A single placebo-controlled study of donepezil at 10 mg daily, as well as open-label study data, have demonstrated a reduction in the severity of cognitive disorders during therapy [462]. However, the potential worsening of motor symptoms requires caution in use and careful patient selection.

Comments: Data on the efficacy of levodopa and its derivatives for correcting motor disorders in CBD are highly ambiguous. However, due to the moderate positive effect shown in several studies and the lack of alternative therapeutic strategies to reduce parkinsonian syndrome in CBD, levodopa and its derivatives should be recommended to all patients. The dose of levodopa and its derivatives in CBD is higher than that for Parkinson's disease therapy and can be increased relatively quickly up to 1500 mg daily. To assess potential clinical benefit before discontinuing the drug due to lack of effect, a trial therapy at a dose of at least 1000 mg for 2 months is recommended. Higher doses can be used quite safely due to the low risk of side effects such as motor fluctuations and drug-induced dyskinesias [463 - 465].

Comments: Due to the combination of parkinsonism, dystonia, and pyramidal signs in patients with CBD, severe upper limb deformity with contracture formation is frequently observed. If these changes significantly impact mobility and the ability to use the hand in daily life, botulinum toxin type A** may be used in accordance with protocols established for the treatment of focal dystonias. The dose and injection frequency are selected individually depending on the severity and prominence of the defect, as well as the muscles involved [466, 467].

Comments: The possibility of supplementary stimulation of the parietal cortex has been studied the most. Several studies used a placebo-controlled design, but with a limited number of enrolled patients. For more convincing recommendations, larger studies with a more representative sample size and the establishment of a unified approved protocol for TMS are required [468 - 470].

Comments: Levodopa and its derivatives can be effective in 30–40% of patients with MSA; however, a sustained positive effect (more than 2 years) persists in only 13% of patients. Dosage is selected individually depending on tolerability and the severity of motor and non-motor manifestations. Given the low risk of complications (fluctuations and dyskinesias), the dose of levodopa and its derivatives can be increased relatively quickly to high doses of 1500 mg daily. The decision that therapy is ineffective should only be made after a three-month trial of levodopa and its derivatives at a dose of at least 1 gram. However, when using high doses, careful monitoring of orthostatic hypotension is necessary, as it can significantly worsen. There is evidence of potential efficacy of rasagiline 1 mg daily in patients with MSA, but studies are limited to a single placebo-controlled trial, which precludes definitive conclusions [473 - 475].

Comments: Not a single systematic study on the efficacy of dopamine receptor agonists has been conducted. Retrospective evaluation demonstrates improvement in no more than 10% of patients, with a high risk of complications in the form of worsening orthostatic hypotension. The single placebo-controlled study of amantadine** showed no improvement, and according to retrospective evaluation, no more than 15% of patients responded to therapy, which also precludes recommending this drug group for correcting parkinsonism in patients with MSA [476].

Comments: According to post-mortem studies, patients with MSA show a decrease in the number of serotonergic neurons, which correlates with the development of respiratory and other disorders in MSA. A placebo-controlled study demonstrated a reduction in motor impairments with the administration of paroxetine**. Although data on the possibility of correcting motor symptoms and respiratory disorders with SSRIs are insufficient, the drugs can be recommended for the management of affective disorders, given that significant depression and anxiety are observed in 70% of patients [481]. Considering coexisting orthostatic hypotension, other antidepressants (such as venlafaxine) may be the drugs of choice. Tricyclic antidepressants are not recommended due to anticholinergic side effects and the risk of exacerbating respiratory disorders and autonomic failure (both orthostatic hypotension and urinary disturbances).

Comments: Occupational therapy and physical rehabilitation are safe, virtually side-effect-free methods for improving patients' quality of life. A controlled study demonstrated the potential to reduce the severity of MSA manifestations using occupational therapy, making it recommendable for all patients with this condition [482].

Comments: To correct orthostatic hypotension in MSA, as in other forms of synucleinopathies such as Parkinson's disease and dementia with Lewy bodies, the administration of #fludrocortisone** starting at a dose of 0.1 mg every other day up to a dose of 0.5 mg daily can be recommended [487]. The drug is recommended for use in conjunction with other mineral supplements (potassium preparations). When using mineralocorticoids, it is crucial to monitor supine hypertension (!), which is the most common and significant side effect of the drug.

Comments: Mirabegron studies were mainly conducted in patients with Parkinson's disease; however, given the common mechanisms of autonomic dysfunction in synucleinopathies, these data can be extrapolated to patients with MSA. Mirabegron is a selective beta-3 adrenergic receptor agonist capable of relaxing smooth muscle and correcting both urinary retention and overactive bladder. #Mirabegron is prescribed at 25 – 50 mg once daily [754]. To date, no systematic studies have been conducted on the efficacy of anticholinergic agents, but they are traditionally used according to general protocols for managing patients with neurogenic voiding dysfunction. All drugs for the treatment of pollakiuria and urinary incontinence must be used strictly under the control of post-void residual volume (!). In severe cases, the use of botulinum toxin type A** may be considered, although data on its efficacy are limited to a small number of observations [492 – 495].

Comments: Data on the feasibility of deep brain stimulation in MSA are limited. According to few studies, the clinical response to neurosurgical intervention is practically absent, which precludes recommending these approaches in patient therapy [496].

Comments: Managing orthostatic hypotension is an important objective in the treatment of all synucleinopathies (MSA, LBD); however, there is no robust evidence base for the efficacy of any particular method. Nevertheless, given the high risk of falls in patients with orthostatic hypotension, increased weakness, and exercise intolerance, all patients must undergo measures to reduce the severity of this autonomic disorder. The safety of non-pharmacological methods makes them the treatment of choice, even in the absence of proven efficacy. [502, 503].

Comments: Parkinsonism syndrome is one of the key criteria for LBD. Approximately 30% of patients show a good clinical response to dopaminergic therapy. Given psychotic and cognitive impairments, the use of other antiparkinsonian drugs is contraindicated. According to observational studies, dopa and its derivatives do not worsen cognitive status, are well tolerated by patients, and do not contribute to sleep deterioration [504, 505].

Comments: Cognitive decline in LBD directly correlates with the degree of cholinergic deficit, as confirmed by neuroimaging data. Therefore, cholinergic therapy can be considered foundational in the treatment of LBD, and ChEIs as the drugs of choice. The efficacy of ChEIs has been confirmed in large meta-analyses, and this applies to their effect not only on cognitive but also on other neuropsychiatric disorders [512]. No significant differences in efficacy were established between rivastigmine**, galantamine**, and donepezil. The number of adverse side effects in the donepezil and galantamine** groups was comparable to the placebo group, indicating their good tolerability and safety. According to a meta-analysis, a significantly higher number of adverse events was noted with the use of rivastigmine**, but this is due to the inclusion of various dosage forms in the analysis: capsules, solution, and transdermal therapeutic system. It was noted that the use of rivastigmine** in the form of a patch—the most popular in clinical practice—is associated with a significantly lower frequency of adverse events than oral drugs, which precludes considering the differences in tolerability among the 3 main ChEIs as significant. Titration of ChEIs should be carried out gradually from starting doses until the "target" effective dose is reached (Appendix A3). If the target dose is insufficiently effective, increasing it to the maximum is possible.

Comments: LBD is not an approved indication for #memantine**, however, the efficacy and safety of #memantine** in such patients have been proven by the results of RCT meta-analyses, although the drug is inferior in efficacy to ChEIs. #memantine** has a minimal number of contraindications, and its tolerability and safety are comparable to placebo, making it the drug of choice in case of contraindications to ChEIs. Titration should be carried out starting at 5 mg and increasing by 5 mg every 1 – 2 weeks until reaching the target dose of 20 mg. Administration of the drug is continued as long as the benefit of its use outweighs the potential risks [516, 755].

Comments: According to meta-analyses, ChEIs significantly reduce the severity of visual hallucinations and other psychotic disorders. Given the risks of prescribing antipsychotic therapy due to hypersensitivity to this group in patients with LBD, the correction of psychotic disorders should always begin with the administration of baseline anti-dementia therapy [517].

Comments: Clozapine is the most studied antipsychotic agent used in LBD. Therapy is initiated at the lowest possible doses: clozapine starting dose is 6.25 mg at bedtime, with a gradual increase if necessary to 12.5 – 75 mg/day (due to the risk of agranulocytosis, white blood cell monitoring is recommended once a week for at least 6 months) [520 – 524, 527, 529, 756].

Comments: #Quetiapine** is the most studied antipsychotic agent used in LBD. Therapy is initiated at the lowest possible doses: quetiapine** starting at 12.5 mg at bedtime, with a gradual increase if necessary to 25 – 200 mg/day (it may provoke arterial hypotension and requires blood pressure monitoring) [520 – 526, 528 – 529, 757].

Comments: The prescription of antipsychotics should occur only when symptom correction cannot be achieved by other approaches (prescribing ChEIs, memantine**, and non-pharmacological methods). Due to hypersensitivity to neuroleptics, the prescription of other drugs of this group (besides #quetiapine** and clozapine), primarily typical antipsychotic agents, is not recommended, as the use of even small doses is fraught with sharp deterioration leading to a condition similar to neuroleptic malignant syndrome or akinetic crisis (in LBD, a similar condition can also be triggered by the withdrawal of dopa and its derivatives, anesthesia, or an intercurrent illness) [520 – 529, 756 – 757].

Comments: No studies on the efficacy of fludrocortisone in patients with LBD have been conducted. However, some positive results obtained in patients with Parkinson's disease make it possible to recommend the use of #fludrocortisone** for the management of orthostatic hypotension, though with a low level of recommendation. Treatment should be initiated at a dose of 0.05 mg every other day with a possible titration up to 0.1 – 0.3 mg daily under the control of supine blood pressure. When using mineralocorticoids, potassium supplements should be prescribed additionally. Supine blood pressure should be monitored throughout the entire therapy period [530, 531].

Comments: The use of solifenacin**, oxybutynin, and tolterodine can worsen cognitive impairment due to their central anticholinergic action.

Comments: When prescribing domperidone, one should bear in mind the possibility of QT interval prolongation, which requires ECG monitoring in patients at risk (concomitant heart diseases, use of other medications contributing to QT prolongation) [549].

Comments: Rapid eye movement sleep behavior disorder (performing purposeful, reality-simulating movements, sleep-talking) quite often requires pharmacological management, as 33–65% of patients with LBD may experience self-injury during nighttime sleep. #Clonazepam** should be prescribed to patients with caution, as it may contribute to the deterioration of cognitive status and an increased risk of falls. Recommending 0.5 mg of #clonazepam** at bedtime is only possible for those patients in whom the risk of sustaining severe injuries during REM sleep outweighs the risks of worsening the disease course [532 - 534].

Comments: As an alternative method, in case of contraindications to the use of clonazepam, melatonin 3–6 mg at bedtime can be used, although its efficacy in managing parasomnia is significantly inferior to clonazepam** [532 - 534]. Some studies have shown a positive effect of AChEIs on rapid eye movement sleep behavior disorder, but the data are limited to case series, which does not allow for definitive conclusions. The administration of dopaminergic agents may contribute to the worsening of clinical manifestations of parasomnia syndrome [535 - 538].

3.2. Dietary therapy in Parkinson's disease

Disturbances in basic metabolic parameters manifest during the initial stages of Parkinson's disease [539 - 541]. A number of studies link the risk of developing Parkinson's disease to dietary patterns. Thus, a retrospective study demonstrated an inverse association between a diet rich in vegetables, fruits, and fish (the so-called Mediterranean diet) and the risk of developing Parkinson's disease [542, 543].

High intake of flavonoids and their subclasses (flavan-3-ols, flavanols, flavones, flavanones, anthocyanins) found in berries and fruits (apples, oranges), tea, and red wine was associated with a lower risk of developing Parkinson's disease in men [544]. On the other hand, excessive dietary intake of iron and animal fats has been shown to increase the risk of developing Parkinson's disease [545].

The dietary behavior of patients with early manifestations of Parkinson's disease was characterized by an excessive intake of saturated fatty acids and a deficiency of unsaturated fatty acids, especially the ω-3 group. There was also a pronounced deficiency in dietary fiber intake, excessive iron intake, and a deficiency in vitamins A, B1, B2, and B5 (PP).

Comments: In Parkinson's disease, changes in metabolic status and methods for their correction using nutritional approaches are of great importance. At the current stage, there are no uniform standards for dietary recommendations in Parkinson's disease.

Dietary therapy in Parkinson's disease is recommended to be based on the concepts of rational nutrition adopted in nutritional science.

Principles of rational nutrition

1. Isocaloric diet (full satisfaction of the body's energy, plastic, and other needs).
2. Optimal ratio of macronutrient intake (proteins, fats, carbohydrates, etc.) depending on anthropometry, age, gender, disease characteristics, etc.
3. Adequate intake of vitamins, trace elements, dietary fiber, and other essential dietary components (nutrients).
4. Optimal dietary regimen (meal frequency, distribution of various macronutrients throughout the day).

Taking into account the principles of rational nutrition and studies characterizing risk factors, the following dietary recommendations are suggested for Parkinson's disease:

1) correction of caloric intake with a reduction in the amount of saturated fats (foods rich in saturated fatty acids (SFAs) include cheeses, marbled meats, beef, pork, mutton and meat products thereof, ice cream, creams, and other confectionery products), reduction of carbohydrates (at the expense of simple carbohydrates and starch: the ratio of total to refined carbohydrates should be at least 7 : 1) to the level of metabolic needs;

2) increasing the quota of fats through polyunsaturated fatty acids, the family of ω-3 and ω-6 polyunsaturated fatty acids (shifting the SFA/PUFA ratio towards polyunsaturated fatty acids (PUFAs)), the sources of which are fatty fish species—mackerel, sardine, herring, halibut, etc.—and vegetable oils (olive, rapeseed, sesame, linseed, soybean, mustard, etc.) [550 - 553];

3) increasing the quota of dietary fiber (containing cellulose, hemicellulose, pectic substances, etc.). Their positive effect is associated with enhanced motor function of the intestine, a probiotic effect, and the elimination of cholesterol entering the small intestinal lumen with bile, which interrupts the hepatoenteral circulation of cholesterol and has a positive effect on lipoprotein metabolism, as well as improves gastrointestinal motility;

4) increasing the quota of vitamin D and B vitamins to the level of metabolic needs, reducing iron consumption to metabolic needs [554 — 556];

5) adequate fluid intake (free fluid 1–1.5 L);

6) frequent fractional meals throughout the day. A 5–6 time meal intake in small portions is recommended. The last meal should be no later than 2–3 hours before bedtime.

Comments: It should be taken into account that dopa drugs and their derivatives are most often used in advanced stages of the disease and compete with amino acids during absorption in the gastrointestinal tract. Therefore, simultaneous intake of protein food with dopa drugs and their derivatives must be avoided.

3.3. Surgical treatment of Parkinson's disease

Neurosurgical treatment of Parkinson's disease includes destructive procedures and deep brain stimulation (DBS) of subcortical brain structures.

The main targets considered for DBS are the subthalamic nucleus (STN), the internal segment of the globus pallidus (GPi), and the ventral intermediate nucleus of the thalamus (VIM). The main advantage of DBS over other surgeries is the possibility of simultaneous bilateral interventions.

Comments: Options for thalamotomy may include stereotactic radiofrequency, radiosurgical, and focused ultrasound thalamotomy. Both procedures—VIM destruction (thalamotomy) or stimulation—allow for almost complete suppression of contralateral tremor, reduce muscle rigidity without affecting bradykinesia. Both procedures can have an adverse effect on speech (left-sided and bilateral procedures cause speech difficulties approximately 3 times more often) and cause ataxia [562]. VIM stimulation can cause paresthesias in the contralateral limbs and face. Radiosurgical thalamotomy can be considered in patients with coagulopathies and is characterized by a delayed treatment effect (3–9 months). Bilateral thalamotomies carry a high risk of transient and permanent neurological complications. Bilateral VIM stimulation can be used for bilateral tremor.

Comments: Unilateral pallidotomy may have an adverse effect on speech. Bilateral pallidotomies carry a high risk of transient and permanent neurological complications.

Comments: STN and GPi stimulation have comparable efficacy in reducing the severity of motor symptoms and improving quality of life, as well as in their effect on mental functions (anxiety and depression). No differences in long-term efficacy between stimulation of both targets regarding motor symptoms have been identified. GPi stimulation leads to a reduction in medicinal dyskinesias, whereas STN stimulation allows for a greater reduction in the equivalent daily dose of levodopa and its derivatives. STN stimulation may be associated with a moderate decline in subcortical-frontal cognitive functions in a portion of patients. There is insufficient data regarding adverse events to recommend a specific target; therefore, the choice of target should be made taking into account technical feasibility, the patient's cognitive status, and the need to reduce the dose of levodopa and its derivatives. In patients with the tremor-dominant subtype of PD and a good response to levodopa and its derivatives, STN stimulation should be considered.

Comments: A levodopa challenge test must be performed when selecting patients for DBS. The challenge test using a regular morning dose of levodopa and its derivatives should be performed after a 12-hour washout of antiparkinsonian medications. If the patient cannot tolerate such a washout period, it is recommended to determine the maximum tolerable duration of withdrawal and maintain this period for all subsequent evaluations. It is recommended to administer 120% of the usual morning dose of levodopa and its derivatives; higher doses of 150% and 200% of the morning dose can be used if necessary. The evaluation should include part III of the UPDRS scale. The difference between the on and off states should be at least 33–50%. Improvement > 50% may be associated with greater overall benefit for most patients. It is important to evaluate axial symptoms (such as gait, freezing, and postural instability) independently of the percentage improvement in the total score. Persistence of axial symptoms in the on state is a predictor of a poor prognosis.

Younger patients with a shorter disease duration may experience greater improvement than older patients with a longer disease duration. Age should not be the primary exclusion factor when selecting for DBS. Patients with a disease duration of less than 4 years should not be considered candidates for DBS, except in situations where the target is disabling tremor.

3.4. Palliative care in Parkinson's disease

Palliative medical care is a complex of measures including medical interventions, psychological support, and nursing care aimed at improving the quality of life of patients and focused on relieving pain and other severe manifestations of the disease [602].

Clinical deterioration in the late stages of the disease, with increasing dependence on medical care, swallowing and respiratory disorders, restricted mobility, and hallucinations, leads to the need for hospitalization in patients with Parkinson's disease [603 - 606].

Management of dysphagia in PD

Dysphagia significantly reduces the quality of life of a patient with PD, leading to aspiration, asphyxia, aspiration pneumonia, malnutrition, and dehydration, especially in the late stages of the disease, and therefore requires correction.

Comments: The feasibility of beverage modification should be considered individually; not all patients are willing to consume thickened liquids (honey or kissel consistency), furthermore, patients with dementia have lower efficacy of this method, and undesirable long-term consequences such as hypohydration and residue pooling in the pharynx are possible, though long-term consequences have been insufficiently studied; it is also advisable to recommend that patients take liquids with the chin tucked, choose food of a convenient consistency, and swallow slowly in small portions [607 — 609].

Data-based speech and swallowing therapy (training of tongue and oropharyngeal muscles) and expiratory muscle strength training may be used to improve swallowing [610 — 612].

Comments: It has been shown that optimizing motor control improves swallowing, and adequate dose escalation of dopaminergic agents often reduces the severity of dysphagia in PD. In addition to dopaminergic agents and their derivatives, dopamine receptor agonists may be used [617].

It is advisable to discontinue medications with anticholinergic properties in PD patients with dysphagia, as they worsen swallowing.

Comments: In case of severe swallowing disorders, short-term use of a nasogastric tube or gastrostomy is advisable [365];

Deep brain stimulation (DBS) has shown positive results in several clinical trials regarding the improvement of swallowing functions in PD; however, according to a 2020 systematic review, current clinical trials lack high levels of evidence [618].

Indications for palliative care

The development of primary outpatient palliative care and home-based palliative care services for relatives and patients with these conditions will lead to a reduction in unjustified hospitalizations in the late stages of the disease.

Timely assessment of the patient's need for palliative care is necessary. In 2016, the European Association for Palliative Care (EAPC) in collaboration with the European Federation of Neurological Societies (EFNS) published a consensus review on the development of palliative care for patients with chronic progressive neurological diseases. The document discusses the need for scientific research in this field, since currently various aspects of palliative care (physical, psychological, social, and spiritual) have only level IV evidence [619].

Comments: to assess the patient's need for palliative care, it is recommended to use the following tools presented in Order No. 605 of the Moscow Healthcare Department dated August 28, 2017 (as amended on May 31, 2021) "On the organization of palliative medical care for the adult population":

- the questionnaire for patients with signs of needing palliative medical care,

- the PPS (Palliative Performance Scale) – a scale for assessing the overall functional performance of patients receiving palliative care,

- the visual analog scale for pain.

Comments: Predictors of the need for palliative care in Parkinson's disease include: progressive deterioration of physical and/or cognitive function despite optimal therapy or a decrease in the efficacy of medical treatment, a critical increase in the duration of OFF periods, a critical escalation of uncontrolled dyskinesias; a critical escalation of postural instability; a critical escalation of mental disorders (dementia, hallucinations, onset of psychoses, depression); a critical escalation of autonomic disorders (orthostatic hypotension); a critical decrease in independence, the need for outside assistance; frequent hospitalizations for falls, urinary tract infections, and pneumonia; weight loss due to dysphagia, loss of appetite, or metabolic changes; gradual withdrawal from socialization, often with increased sleepiness; acceleration of the rate of functional decline; critical swallowing problems (dysphagia) leading to recurrent aspiration pneumonia, sepsis, dyspnea, or respiratory failure; speech problems: increasing difficulties in communication. The decision on the setting for the provision of palliative medical care (outpatient, inpatient, or mobile team) is made based on the regional routing order [633 - 636].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Medical rehabilitation, medical indications and contraindications for the use of rehabilitation methods in Parkinson's disease

Rehabilitation for Parkinson's disease, in addition to drug therapy, can improve mobility, walking, balance, and muscle strength in patients.

The goal of rehabilitation in Parkinson's disease is to improve the quality of life by maintaining or increasing the patient's independence, safety, and well-being. This is achieved by preventing a sedentary lifestyle and falls, improving daily activities, and reducing limitations in daily functioning.

General principles of rehabilitation for patients with Parkinson's disease include:

1. Personalized approach to rehabilitation

2. Systematic approach to the implementation of rehabilitation measures

3. Drug support of the rehabilitation process

4. Compliance with the basic principles of medical rehabilitation (evidence-based approach, staging, continuity, succession)

5. Initiation of early rehabilitation

Personalized approach to the rehabilitation of patients with Parkinson's disease:

1. Examination of the patient with assessment of motor (physical activity, transfers, postural stability, muscle strength, range of motion, gait) and non-motor functions

2. Formulation of a rehabilitation diagnosis according to the ICF

3. Analysis (setting rehabilitation goals)

4. Individual rehabilitation program

5. Assessment of efficacy

6. Follow-up observation

The main long-term objectives of rehabilitation in patients with Parkinson's disease are:

1. ensuring the safety and independence of the patient in daily life with a focus on transfers, postural stability, muscle strength, range of motion, and gait;

2. maintaining or improving motor activity;

3. maintaining and increasing endurance;

4. prevention of falls;

5. prevention of pressure ulcers;

6. amelioration of cognitive impairments

7. amelioration of emotional disorders

When selecting patients for rehabilitation measures, it is necessary to:

- A neurologist, when referring for rehabilitation, indicates the severity of Parkinson's disease (disease stage), the presence of motor fluctuations, dyskinesias, freezing, postural disorders, non-motor disorders (orthostatic hypotension, urinary disorders, cognitive impairment, etc.), and comorbidities (e.g., osteoporosis and other diseases that reduce physical activity, such as arthritis, heart failure, and COPD). The neurologist should be the coordinator of the entire rehabilitation process from diagnostics to the drafting of the individual rehabilitation plan for patients with Parkinson's disease.

- Assess motor and non-motor functions, as well as activity and participation, and environmental factors contributing to functioning in Parkinson's disease in accordance with the ICF, and using validated scales and questionnaires. The assessment is carried out by the patient themselves as well as by a physical and rehabilitation medicine physician, speech-language pathologist, clinical psychologist, occupational therapist, and psychotherapist. Assessment according to the ICF will make it possible to establish a rehabilitation diagnosis and determine short-term rehabilitation goals.

- Identify factors, namely the presence of falls and freezing of gait, that may limit the use of certain rehabilitation methods when collecting patient complaints. If the patient exhibits cognitive impairments, a relative or caregiver should be involved to obtain additional information.

- Assess motor functions during a neurological examination: physical activity, transfers, postural stability, muscle strength, muscle tone, range of motion, gait, presence of tremor, involuntary movements, and motor fluctuations; cognitive and emotional functions; unilateral or bilateral symptoms. The presence of motor fluctuations leads to fluctuations in motor activity in patients throughout the day. Therefore, during the examination, the physical and rehabilitation medicine physician must know the state the patient is in ("ON" or "OFF"). To record fluctuations in motor activity throughout the day, the patient should keep a diary reflecting the "ON" and "OFF" periods.

What needs to be considered when carrying out rehabilitation measures in patients with Parkinson's disease:

• the presence of "ON" and "OFF" periods during the day with the use of various rehabilitation methods, duration, and intensity of sessions;

• assessment of cognitive functions and the patient's age, which determine the degree of complexity in choosing a rehabilitation method;

• the presence of freezing of gait, which determines the choice of the rehabilitation method;

• the presence of fatigue, which determines the choice of the rehabilitation method, duration, and intensity of sessions.

Relative contraindications to rehabilitation in patients with Parkinson's disease:

• in patients after DBS (deep brain stimulation), diathermy (shortwave, microwave therapy) is contraindicated.

• the presence of psychotic disorders and pronounced cognitive impairments

Features of rehabilitation in the presence of the "ON-OFF" phenomenon

- In the "ON" period, there are no restrictions on the use of recommended rehabilitation methods. High-intensity aerobic loads should not last longer than 10 minutes.

- In the "OFF" period, dual-tasking should be avoided during the session. A dual task can have a negative impact on gait and balance, which can lead to a fall. Avoiding dual-tasking while walking can reduce falls.

Conditionally, rehabilitation methods in Parkinson's disease can be divided into: 1) a set of various techniques for restoring and maintaining various motor functions (motor rehabilitation); 2) biofeedback (BFB) and virtual reality technologies; 3) cognitive training to improve cognitive functions; 4) social support and psychotherapy; 5) occupational therapy to maintain and restore daily living skills; 6) speech therapy correction.

The main methods of motor rehabilitation include therapeutic exercises, Nordic walking, treadmill training, dance therapy, and Chinese tai chi gymnastics.

Therapeutic exercises

Comments: Most studies have investigated the effect of physical exercise on functional mobility in Parkinson's disease [637 - 662]. In addition, the effect on muscle strength using high-amplitude movements or on gait using Nordic walking was evaluated.

The main objectives of applying physical exercises are to improve walking parameters (stride length, walking speed and duration), range of motion, physical performance (strength, mobility and endurance), and balance. Most commonly, a set of exercises is used, including active or passive movements for the limbs and spine, stretching, strength training, and walking. Physical exercises allow for a high degree of certainty in influencing motor functions, walking speed, and muscle strength. With a moderate degree of certainty — functional mobility and balance. With a lower degree of certainty — falls, freezing of gait, stride length, walking duration, turning speed, balance efficacy, level of daily activity, and quality of life.

The duration of the outpatient rehabilitation course is a minimum of eight weeks, three times a week for 45 minutes. Individual or group sessions are possible. Subsequently, rehabilitation is continued at home according to a developed program.

Treadmill training

Comments: In studies, treadmill training (running track) was used both as a standalone method and as part of comprehensive rehabilitation for Parkinson's disease [663 - 681]. In most studies, treadmill training was performed using overhead safety harnesses. Only one study evaluated treadmill training at home without safety harnesses in patients without postural instability and without freezing of gait. Due to the fact that patients with Parkinson's disease exhibit gait impairments in the form of reduced speed and range of motion, proprioception and tactile function impairments, it is preferable to use treadmill training with biofeedback. Treadmill training with a high degree of certainty affects the increase in walking speed and stride length. Treadmill training with a moderate degree of certainty affects walking duration and balance. Treadmill training with a low degree of certainty may affect functional mobility during walking, motor functions, and an increase in knee extensor muscle strength. Treadmill training is contraindicated in patients with cognitive impairment and freezing of gait without the use of overhead safety harnesses and supervision by a rehabilitation specialist. The duration of the outpatient rehabilitation course should be a minimum of four weeks, three times a week for 30 minutes.

Dance therapy

Dance therapy is considered as an additional form of exercise for patients with Parkinson's disease. The most common type of dance therapy is ballroom dancing. Dance therapy is indicated for patients with freezing of gait, as music provides an external rhythm that can be viewed as a cueing technique. Since dance movements are multi-tasking and require learning, they can be attributed to both motor and cognitive rehabilitation.

Comments: Dance therapy with a moderate degree of certainty affects functional mobility and balance. With a low degree of certainty, it affects walking speed, stride length, walking duration, freezing of gait, motor functions, and quality of life. Dance therapy allows for an increase in the range of motion, complex sequential movements, steps in different directions, backward walking, walking in confined spaces, single-leg stance balance, weight shifting, and controlled center of mass shifting.

The choice of dance for the patient will depend on the patient's individual characteristics.

Tai Chi gymnastics

Comments: Tai Chi gymnastics has been used to improve balance and gait in patients with Parkinson's disease. Tai Chi is a safe rehabilitation method with sustained long-term efficacy. However, learning Tai Chi is difficult. Tai Chi with a high degree of certainty affects the improvement of motor functions. With a moderate degree of certainty, it affects the number of falls, balance, walking speed, stride length, walking duration, functional mobility, and muscle strength.

The efficacy of an outpatient rehabilitation course is a minimum of 24 weeks, twice a week for 60 minutes.

Correction of respiratory function

Respiratory muscle training is a technique aimed at improving respiratory muscle function using specialized exercises. In particular, inspiratory muscle training has been shown to improve respiratory function and can reduce dyspnea on exertion.

Two controlled studies evaluating the efficacy of physical exercises for reducing respiratory impairments in Parkinson's disease have been published. However, neither study showed efficacy. Therefore, there are currently no evidence-based recommendations.

Management of pain syndrome

No studies have been conducted on the impact of rehabilitation methods on pain syndrome in Parkinson's disease. Therefore, there are currently no recommendations. However, musculoskeletal pain frequently occurs in Parkinson's disease, and when other causes are excluded, rehabilitation may be indicated. Rehabilitation methods are based on an understanding of pain mechanisms, including eliminating the impact of fear on pain and the importance of maintaining physical activity. The visual analogue scale for pain can be used for assessment. Management of pain syndrome may include: 1) physical exercises for musculoskeletal and neuropathic pain, 2) pain relief techniques using TENS and manual therapy, 3) peripheral desensitization techniques, 4) motor imagery and mirror therapy, 5) cognitive strategies.

Motor relearning

Motor relearning is defined as "a set of processes associated with practice leading to relatively permanent changes in motor skill." These processes involve the interaction of the frontoparietal cortex, basal ganglia, and cerebellum. There are three phases of motor learning:

1. Fast learning (cognitive phase): the process of acquisition with significant improvement in motor functions during the session

2. Automation (associative phase): movements become precise, performed without excessive tension, requiring minimal cognitive resources, stable over time and resilient, for example, when performing dual tasks

3. Stabilization (retention/autonomous phase): the motor skill is formed, movements are easily performed with a high degree of coordination and automation

The ability to perform complex tasks and coordinate complex conditions depends on automaticity. Automaticity depends on the function of the basal ganglia, and therefore this function is largely impaired in patients with Parkinson's disease. Despite these disorders, patients are capable of motor learning because the basal ganglia play a key role in automation. However, the retention (consolidation) of motor skills is difficult for patients with Parkinson's disease. The ability to develop a new skill can be achieved by compensating for basal ganglia dysfunction through the activation of other brain structures, such as the cerebellum. Since the learning potential is believed to decrease with disease progression, the greatest benefits can be obtained in the early and moderate stages of the disease. Taking into account the general principles of motor relearning and using external cues will improve concentration, automation, and stabilization.

Motor control

In healthy individuals, motor areas of the cortex are involved not only during the actual execution of a movement, but also during motor imagery (mental simulation of movement) or simply observing someone performing a movement (action observation). Consequently, action observation and motor imagery can lead to improved walking skills. Both strategies rely heavily on received sensory information and are thought to engage the same mechanisms via mirror neurons. Mirror neurons are involved in the execution of an action, but are also activated during the imagery of the same action, which helps activate the premotor cortex.

Training in compensatory movement strategies

The basis of compensatory strategy training in walking is to compensate for impairments through internal (automatic) generation of behavior. It includes cueing, attention focusing, and compensatory strategies for complex motor acts.

Comments: Auditory and visual stimuli were used in the studies. Compensatory strategies utilizing auditory and visual stimuli have a high level of certainty in affecting walking speed. They have a moderate level of certainty regarding step length, motor functions, and freezing of gait. They have a low level of certainty regarding functional mobility, balance, and quality of life. An outpatient training course in compensatory strategies lasts at least three weeks, three times a week for 30 minutes.

Speech therapy in PD

Parkinson's disease leads to speech and swallowing disorders, which are particularly pronounced in the later stages of the disease. Speech becomes monotonous, devoid of emotional coloring, and hypophonic. A fading voice is noted during conversation. Articulation is impaired, particularly in the pronunciation of consonants, which is explained by the narrowing of the vocal tract and reduced mobility of the lips, lower jaw, and tongue due to muscle rigidity involved in speech production. Patients with PD also experience impaired speech tempo. Against the background of a general decrease in speech speed, propulsion (episodes of accelerated speech), prolonged pauses, lengthening of the speech initiation moment, and reduced speech fluency may occur.

Comments: Patients with PD exhibiting speech impairments are indicated for speech therapy sessions utilizing articulation exercises, phonetics work, speech therapy massage, and a multisystem biofeedback (BFB) speech trainer for voice amplification. One of the most widely used methods for treating speech disorders associated with Parkinson's disease is the Lee Silverman Voice Treatment (LSVT) [720].

Additionally, for dysphagia and dysarthria, the use of sessions on the VocaSTIM neuromuscular electrophonopedic stimulation device is recommended.

4.2. Sanatorium-resort treatment, medical rehabilitation methods based on natural therapeutic factors

In accordance with Order of the Russian Ministry of Health No. 1029n dated September 28, 2020, "On Approval of the Lists of Medical Indications and Contraindications for Sanatorium-Resort Treatment," Parkinson's disease is not a contraindication for sanatorium-resort treatment [733].

Sanatorium-resort treatment is organized in accordance with Order of the Russian Ministry of Health No. 279n dated May 5, 2016, "On Approval of the Procedure for Organizing Sanatorium-Resort Treatment," as amended by Order of the Russian Ministry of Health No. 1028n dated September 25, 2020.

The duration of sanatorium-resort treatment ranges from 14 to 21 days.

5. Prevention and Dispensary Observation

Main risk factors for the development of Parkinson's disease non-modifiable: age, positive family history (the probability of a genetic variant is higher if the age of onset is under 40 years), male sex, contact with herbicides and pesticides, heavy metals (magnesium, manganese, iron), race (Caucasian), frequent severe traumatic brain injuries. Evidence-based studies on methods for preventing Parkinson's disease have not been conducted.

Taking into account the progression of the disease, one can distinguish: - non-modifiable factors indicating rapid progression: 1) late age of disease onset; 2) presence of severe depression; 3) dementia; 4) comorbid problems; 5) akinetic-rigid form; and modifiable factors: 1) low physical activity and 2) falls. Combined with an increased risk of osteoporosis, a fall can lead to fractures or other trauma and the development of astasophobia, resulting in a decreased level of physical activity and further increasing the causes of falls.

The main complications of Parkinson's disease are pulmonary embolism (PE), congestive or aspiration pneumonia, pressure ulcers, urinary tract infection, malnutrition, immobilization, and respiratory failure.

Prevention of complications of Parkinson's disease comes down to measures aimed at increasing physical activity and preventing complications of the disease (PE, congestive or aspiration pneumonia, pressure ulcers, urinary tract infection, malnutrition). Numerous studies have shown that regular physical activity, active intellectual engagement, and cognitive training starting from early stages have a positive effect on motor, cognitive, and emotional functions.

Stages of initiation and subsequent long-term use of levodopa+carbidopa intestinal gel

1. Screening (up to 14 days) – at this stage, necessary examinations are performed to confirm that the patient is indicated for levodopa+carbidopa intestinal gel therapy and has no contraindications to surgery.
2. Hospitalization stage (up to 14 days) – includes two stages:

1. Stage in the neurological department: placement of a nasoduodenal tube, administration of levodopa+carbidopa intestinal gel, titration and dose adjustment using a special external pump located in the projection of the anterior abdominal wall and attached via a special pouch. The titration stage lasts up to 9 days.
2. Stage in the surgical department: placement of a permanent gastroduodenal tube via percutaneous gastroduodenostomy under endoscopic and/or fluoroscopic control, lasting up to 5 days.

1. Long-term treatment period – following the placement of the gastroduodenal tube, the prolonged treatment period begins. This treatment can last indefinitely, for as long as it remains clinically justified.
2. Frequency of follow-up outpatient visits is 1 time every 3–6 months.

The role of the multidisciplinary team during the stages of initiation and subsequent long-term use of levodopa+carbidopa intestinal gel:

1. Neurologist (outpatient clinic):

- an outpatient neurologist who collects and analyzes baseline data, medical history, clinical symptoms, compliance of symptoms with advanced stages of Parkinson's disease, determines the need for initiating invasive therapy, and refers the patient for consultation followed by hospitalization in the specialized neurological center department.

2. Neurologist (specialized neurological center):

- re-evaluates clinical symptoms for compliance with criteria requiring invasive therapy. Subsequently, an invasive treatment method is chosen by the physician together with the patient and/or caregiver. Issues referrals for laboratory and instrumental examinations necessary for further hospitalization. Issues a hospitalization referral. Performs follow-up monitoring of the patient after pump installation and transition to routine therapy, provides consultative support at all stages of pump and tube installation, and trains patients and caregivers on the specifics of operating and caring for the stoma, tubes, and pump.

3. Surgeon: performs a preliminary assessment of the patient's eligibility for gastrostomy with pump connection for drug delivery, provides monitoring in the early postoperative period, and offers consultative support during the routine therapy phase.

4. Endoscopist: performs endoscopy at the screening stage to rule out contraindications to endoscopic intervention. Participates in the placement of nasojejunal and gastrostomy tubes, and provides consultative support in the early postoperative period and during the routine therapy phase.

5. Radiologist: provides support during the nasojejunal and gastrostomy stages to monitor tube placement, and provides subsequent consultative support when indicated.

6. Anesthesiologist: assesses contraindications to anesthesia, provides anesthetic management at the nasojejunal stage (if necessary) and during gastrostomy placement, and provides consultative support during the routine therapy phase.

Management of patients with PD after neurosurgical treatment

Comments: The decision regarding the timing of postoperative programming depends on available resources and convenience in individual centers. Initial programming is performed at 1–4 weeks. The delayed start of primary programming is associated with the microlesion effect after surgery; therefore, the patient must be informed about potential fluctuations in condition after surgery, as well as during the first few months after electrode implantation. The need to adjust the stimulation program and therapy thereafter is driven by disease progression

The main stages of initial programming are:

- initiating programming in the OFF period, typically in the morning, before taking the first dose of antiparkinsonian medications

- clarifying anamnestic data regarding the clinical course features of PD, pharmacotherapy, and surgical implantation details (stimulator type, results of intraoperative microelectrode recording and test stimulation)

- checking the resistance (impedance) of each electrode contact (impedance values less than 100 and greater than 4000 ohms indicate system malfunction)

- starting programming with a monopolar mode, 130 Hz frequency, 60 µs pulse width.

- evaluating the stimulation of each electrode contact for each side regarding core symptoms (hypokinesia, rigidity, and tremor), identifying side effects, and determining the so-called "therapeutic window". (rate of reduction in severity of core symptoms: rigidity — seconds, tremor — seconds to minutes, hypokinesia — minutes to hours)

- amplitude adjustment step of 0.2 - 0.5 V. Setting the minimum effective amplitude

- administration of dopaminergic drugs and their derivatives (typically at a 1.5 - 2 times reduced dose) and assessment of dyskinesia severity

- subsequent days: additional program adjustment and optimization of antiparkinsonian therapy. Patients may use several programs alternately at home to choose the most effective one

A consultation with a neurologist performing the initial programming can take from 60 to 90 minutes, as it requires adjusting the program in both the OFF and ON periods.

Indications for adjusting the stimulation program and pharmacotherapy during DBS include:

- insufficient effect on motor and/or non-motor symptoms;

- stimulation side effects

Dispensary follow-up (Active surveillance)

All patients with PD require follow-up dispensary observation, the purpose of which is to achieve improvement or stabilization of functional status and the clinical course of the underlying disease, prevent progression or acute decompensation, and improve the quality of life of the patient and caregivers. The tasks of dispensary observation include: adjusting the underlying disease therapy; assessing comorbidity and, if necessary, addressing the need for further evaluation and consultations with related specialists. Dispensary observation is carried out in accordance with Order of the Russian Ministry of Health No. 173n dated March 29, 2019, "On Approval of the Procedure for Dispensary Observation of Adults." All older patients with cognitive impairment are recommended to undergo dynamic observation by a neurologist, and as indicated by a psychiatrist or general practitioner every 3–6 months to assess condition dynamics, optimize treatment and rehabilitation. Assessment of comorbid conditions and their therapy is carried out at least once every 6 months or as needed.

6. Organization of Medical Care

Comments: The organization of separate specialized clinical and diagnostic offices, federal and regional centers is the only effective measure for organizing highly specialized care for patients with PD, as well as a way to collect up-to-date information on the prevalence of the disease, rehabilitation, and other activities.

Comments: Not all patients require hospitalization in a 24-hour inpatient facility for treatment.

Stages of rehabilitation care for patients with PD

7. Additional Information

The course and outcome of Parkinson's disease are influenced by both adherence to basic pharmacotherapy, timely compensation of concomitant somatic diseases, and proper organization of long-term care.

It is necessary to monitor patient adherence to therapy, as independent intake of medications at the right time and in the right dosages is difficult for such patients. Skipping doses or temporary discontinuation of symptomatic treatment by the patient negatively affects the disease course and prognosis.

As Parkinson's disease progresses, non-pharmacological measures become increasingly important, playing a predominant role at the terminal stage, which includes both medical and non-medical care and depends on the coordination of medical and social services.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Alferova V.V. – D.Sc. in Medicine, Chief Research Officer, Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Presidium of the All-Russian Society of Neurologists
2. Amosova N.A. – D.Sc. in Medicine, Neurologist, Chief Physician, Clinical Hospital of the Presidential Administration of the Russian Federation, Member of the National Society for the Study of Parkinson's Disease and Movement Disorders
3. Bogdanov R.R. – D.Sc. in Medicine, Professor, Department of Neurology, Moscow Regional Research Clinical Institute (MONIKI) named after M.F. Vladimirsky, Member of the National Society for the Study of Parkinson's Disease and Movement Disorders
4. Bril E.V. – Ph.D. in Medicine, Associate Professor, Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO), Member of the National Society for the Study of Parkinson's Disease and Movement Disorders
5. Vasenina E.E. – Ph.D. in Medicine, Associate Professor, Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO)
6. Gekht A.B. – D.Sc. in Medicine, Professor, Department of Neurology and Neurosurgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Director of the Solovyov Research and Practical Center for Mental Health of the Moscow Healthcare Department, Member of the Presidium of the National Society for the Study of Parkinson's Disease and Movement Disorders
7. Gamaleya A.A. – Neurologist, Scientific-Consultative Department, Burdenko National Medical Research Center of Neurosurgery of the Russian Ministry of Health, Moscow
8. Gusev E.I. – D.Sc. in Medicine, Academician of the Russian Academy of Sciences, Professor, Head of the Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, President of the All-Russian Society of Neurologists
9. Emelin A.Yu. – D.Sc. in Medicine, Professor, Department of Nervous Diseases, Kirov Military Medical Academy
10. Zalyalova Z.A. – D.Sc. in Medicine, Professor, Department of Neurology and Rehabilitation, Kazan State Medical University of the Russian Ministry of Health, Head of the Republican Clinical-Diagnostic Center for Extramyramidal Pathology and Botulinum Therapy and the Consultative-Diagnostic Center for Extramyramidal Pathology of Kazan, Member of the Presidium of the National Society for the Study of Parkinson's Disease and Movement Disorders, Member of the Presidium of the Interregional public organization of specialists in botulinum therapy (MOOSBT)
11. Illarioshkin S.N. – D.Sc. in Medicine, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director for Science, Research Center of Neurology, Head of the Department of Brain Research, President of the National Society for the Study of Parkinson's Disease and Movement Disorders.
12. Ivanova G.E. – D.Sc. in Medicine, Professor, Department of Rehabilitation and Sports Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chairman of the Presidium of the All-Russian Association for the Promotion of Medical Rehabilitation Development "Union of Rehabilitologists of Russia", Chief Specialist in Medical Rehabilitation of the Russian Ministry of Health, Head of the Department of Medical and Social Stroke Rehabilitation, Research Institute of Cerebrovascular Pathology and Stroke, Pirogov Russian National Research Medical University of the Russian Ministry of Health
13. Katunina E.A. – D.Sc. in Medicine, Professor, Department of Neurology and Neurosurgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the National Society for the Study of Parkinson's Disease and Movement Disorders
14. Levin O.S. – D.Sc. in Medicine, Professor, Head of the Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO), Member of the Board of the All-Russian Society of Neurologists, Vice-President of the National Society for the Study of Parkinson's Disease and Movement Disorders
15. Litvinenko I.V. – D.Sc. in Medicine, Professor, Head of the Department of Nervous Diseases, Kirov Military Medical Academy, Vice-President of the National Society for the Study of Parkinson's Disease and Movement Disorders
16. Martynov M.Yu. – D.Sc. in Medicine, Corresponding Member of the Russian Academy of Sciences, Professor, Chief freelance Specialist in Neurology of the Russian Ministry of Health, First Deputy General Director of the Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency (FMBA of Russia), Professor of the Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Scientific Secretary of the All-Russian Society of Neurologists
17. Nodel M.R. – D.Sc. in Medicine, Professor of the Department of Nervous Diseases and Neurosurgery, Leading Research Officer, Neurology Research Department, Research Institute of Clinical Medicine named after N.V. Sklifosovsky (Sechenov University), Member of the National Society for the Study of Parkinson's Disease and Movement Disorders
18. Popov G.R. – Senior Research Officer, Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, and Neurologist, Solovyov Research and Practical Center for Mental Health of the Moscow Healthcare Department
19. Pavlov N.A. – Ph.D. in Medicine, Leading Research Officer, Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Presidium of the All-Russian Pirogov Society of Neurologists of the Russian Ministry of Health
20. Rachin A.P. – D.Sc. in Medicine, Professor, Deputy Director for Science, Head of the Department of Neurorehabilitation and Clinical Psychology, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health
21. Skripkina N.A. – Ph.D. in Medicine, Associate Professor, Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO)
22. Smolentseva I.G. – D.Sc. in Medicine, Professor, Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO), Head of the Treatment and Rehabilitation Center of the Clinical Hospital of the Presidential Administration of the Russian Federation, Member of the Presidium of the National Society for the Study of Parkinson's Disease and Movement Disorders
23. Tomsky A.A. – Ph.D. in Medicine, Senior Research Officer, Head of the Functional Neurosurgery Group, Burdenko National Medical Research Center of Neurosurgery of the Russian Ministry of Health
24. Usachev D.Yu. – D.Sc. in Medicine, Corresponding Member of the Russian Academy of Sciences, Professor, Director of the Burdenko National Medical Research Center of Neurosurgery of the Russian Ministry of Health, President of the Association of Neurosurgeons of Russia
25. Fedorova N.V. – D.Sc. in Medicine, Professor, Department of Neurology, Russian Medical Academy of Continuous Professional Education (RMANPO)
26. Fesyun A.D. – MD, Professor, Director of the National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health
27. Yakhno N.N. - MD, Professor, Academician of the Russian Academy of Sciences, Scientific and Educational Clinical Center of Neurology, Sechenov First Moscow State Medical University, Kozhevnikov Clinic of Nervous Diseases

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Neurologist of medical organizations providing care in outpatient and inpatient settings.

2. Geriatrician of medical organizations providing care in outpatient and inpatient settings.

3. Psychiatriatrist of medical organizations providing care in outpatient and inpatient settings.

Table P1. Scale for evaluating levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table P2. Scale for evaluating levels of evidence (LE) for methods of prevention, treatment and rehabilitation (preventive, therapeutic, and rehabilitative interventions)

Table P3. Scale for evaluating grades of recommendation (GR) for methods of prevention, diagnostics, treatment, and rehabilitation (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The guideline update mechanism provides for their systematic review—at least once every three years or upon the emergence of new information on the management tactics of patients with this disease. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The submitted proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

Diagnostic criteria for vascular parkinsonism

A. Diagnostic criteria for parkinsonism syndrome:

Diagnosis of parkinsonism syndrome is possible if at least two of the four main symptoms are present: hypokinesia, rigidity, resting tremor, postural instability. Hypokinesia (as the leading manifestation of parkinsonism, which usually determines the severity of the patient's condition) is often singled out as an obligate symptom.

B. Diagnostic criteria for cerebrovascular disease:

The presence of cerebrovascular disease is confirmed by identifying vascular risk factors (in particular, arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, etc.), signs of cardiovascular diseases (e.g., coronary artery disease, heart diseases with a high risk of cardiogenic embolism, obliterating vascular disease of the lower extremities, etc.), stenosing lesions of precerebral or cerebral arteries (vascular bruit over the carotid arteries on auscultation, data from ultrasound methods, angiography, or MR angiography), and a history of stroke/TIA episodes. However, decisive importance is attached to CT and MRI data, which confirm the fact of vascular brain damage and clarify its localization and extent.

C. Establishing a causal relationship between parkinsonism and cerebrovascular disease, proven by:

1) the course features of parkinsonism

- acute or subacute onset, fluctuating course with periods of prolonged stabilization and regression, onset in the first six months after a stroke

2) correspondence between clinical and neuroimaging data: detection by CT and MRI of changes in areas "strategic" for parkinsonism [bilateral ischemic and/or hemorrhagic lesions in the putamen and globus pallidus, bilateral confluent subcortical leukoaraiosis, ischemic or hemorrhagic lesions in the frontal lobes (usually bilateral), thalamus, and midbrain (unilateral or bilateral)]

D. Absence of anamnestical, clinical, and neuroimaging signs indicating a different etiology of parkinsonism, such as:

• Absence of vascular changes on MRI,
• Inconsistency between the nature and degree of clinical manifestations and the localization and extent of vascular brain damage (according to MRI): absence of involvement of "strategic zones",
• Persistent high efficacy of dopa and its derivatives over several years,
• Development of downward gaze palsy in the absence of upward gaze palsy,
• Signs of progressive autonomic failure,
• Early development of visual hallucinations,
• Presence of midbrain and putamen atrophy and other signs of PSP and MSA (according to MRI).

Diagnostic criteria MDS-PSP: core clinical features

avPPA - agrammatic variant of primary progressive aphasia

Clinical subtypes of PSP according to MDS-PSP criteria

PSP-RS – Richardson's syndrome, PSP-P – parkinsonian variant, PSP-PGF – progressive gait freezing, PSP-FTD – frontotemporal dementia, PSP-OM – ocular motor variant, PSP-PPA/SP – progressive primary aphasia or speech apraxia, PSP-CBS – corticobasal syndrome, PSP-PI – postural instability; *Additional features 1) levodopa and its derivatives resistance, 2) hypokinetic spastic dysarthria, 3) dysphagia, 4) photophobia; **designated as probable 4R-tauopathy.

MSA Diagnostic Criteria

Table. Clinical diagnostic criteria for dementia with Lewy bodies (after McKeith et al., 2017)

* Impairment in attention, executive, and visuospatial functions is often pronounced early in the disease, whereas memory impairment may become prominent or persistent later as the disease progresses.

** A probable LBD diagnosis cannot be established on the basis of indicative biomarkers alone.

If dementia occurs in the setting of fully established Parkinson's disease, the term "Parkinson's disease dementia" (PDD) should be used. In clinical practice, the term that best fits the clinical situation should be used; both clinical phenotypes may be collectively referred to as "Lewy body disease." For research studies requiring differentiation between LBD and PDD, the 1-year rule between the onset of dementia and parkinsonism is still recommended.

Neuroimaging features of multiple systems atrophy based on MRI data (levels II and III of evidence):

Neuroimaging features of progressive supranuclear palsy based on MRI data (levels II and III of evidence):

Midbrain atrophy

Indirect signs of atrophy:

Reduced midbrain diameter (< 14 mm of reference values)

Abnormal midbrain shape (concave compared to convex in healthy individuals)

Midbrain tegmentum shape (penguin silhouette or hummingbird sign)

Decreased midbrain-to-pons ratio

Dilatation of the third ventricle portion

Atrophy of the superior and middle cerebellar peduncles

Signal hyperintensity in the superior cerebellar peduncles (FLAIR sequence)

Signal hyperintensity in the globus pallidus

Signal hyperintensity in the red nucleus

Putaminal atrophy

Frontal and parietal atrophy

Titration of antiparkinsonian therapy

1. Titration of dopa and its derivatives

Dopa and its derivatives are initially prescribed at a levodopa-equivalent dose of 50 mg twice daily. The dose is then gradually increased by 50 mg every 5–7 days (administered at least three times daily) until the optimal dose for each patient is reached

1. Titration of #pramipexole** [761]

1. Pramipexole** titration in PD

1. Ropinirole titration

Week 1 2 3 4

Daily dose (mg) 2 4 6 8

The daily dose may be further increased by 4 mg at 1–2 week intervals (until the desired therapeutic effect is achieved). The maximum daily dose is 24 mg/day.

1. ChEPI titration

* - PR – prolonged release

Appendix B. Physician Action Algorithms

1. Algorithm for differential diagnosis of parkinsonism

   

   2. Management algorithm for early-stage Parkinson's disease

   

   3. Algorithm for the treatment of depression in patients with Parkinson's disease

   

   4. Management algorithm for constipation in Parkinson's disease

   *Enemas and manual techniques may be required for individual patients with PD with severe constipation (not included in the algorithm).

   

2. 5. Algorithm of indications for surgical treatment in Parkinson's disease

3. 

4. 6. Algorithm for examining a patient with DBS and initial neurostimulation program selection

5. 

Appendix C. Patient Information

What you need to know about Parkinson's disease

1. What is Parkinson's disease?

Parkinson's disease (PD) is a slowly progressive chronic brain disease manifested by slowness and impoverished motor pattern, increased muscle tone, postural instability, gait disturbances, and a wide range of non-motor symptoms.

The disease is named after the English physician James Parkinson, who demonstrated phenomenal clinical observation skills and managed to describe almost all the main signs of the disease in his "Essay on the Shaking Palsy", published in 1817. The name "shaking palsy" reflected the paradoxical combination of excessive involuntary movements with a peculiar "weakness" – impaired fine limb movements, stiffness, general slowness, and an impoverished motor pattern.

It was not until 1912 that the German pathomorphologist Friedrich Lewy discovered specific inclusions in certain brain structures in patients with Parkinson's disease.

Finally, in 1919, the prominent Russian neurologist K.N. Tretiakoff described similar inclusions in the neurons of the substantia nigra, naming them Lewy bodies. Thus, it was revealed that the cause of Parkinson's disease is the dysfunction and reduction in the number of cells containing the dark neuromelanin pigment and producing dopamine. These cells are concentrated in the brain in an area called the substantia nigra. In fact, their accumulation gives this structure its dark shade, reflected in its name. The dopamine secreted by these cells, which serves to transmit excitation from one cell to another, keeps the entire system of subcortical structures working properly, ensuring the regulation of movements, cognitive activity, and affective state (mood, motivation, etc.).

Dopamine deficiency in the deep (subcortical) regions of the brain is the key biochemical defect in Parkinson's disease. The main motor manifestations of the disease are associated with it, and correcting dopamine deficiency using levodopa and its derivatives and other dopaminergic agents serves as the main direction in its treatment.

Parkinsonism syndrome with similar symptoms can also occur in vascular or traumatic lesions of the subcortical brain structures, brain tumors, enlargement of the brain ventricles (hydrocephalus), adverse drug reactions, and some other chronic brain diseases.

However, Parkinson's disease is the most frequent cause of parkinsonism syndrome, accounting for up to 80% of its cases. Overall, the prevalence of Parkinson's disease ranges from 120 to 180 cases per 100,000 population, and at age 75 and older, at least 2% of people suffer from it. Parkinson's disease most often manifests after the age of 50, but cases of disease onset at an earlier age are not uncommon. Men are affected slightly more often than women.

The main clinical manifestation of Parkinson's disease is parkinsonism syndrome, which includes the following complex of symptoms:

• slowness of all movements (hypokinesia);

• impaired fine motor skills of the limbs;

• fatigability of rapid alternating movements of the hands and feet;

• stiffness (increased tone) of muscles (muscle rigidity);

• tremor of the hands and legs, most pronounced at rest;

• postural instability and change in posture (most frequently stooping);

• shortened step length and shuffling gait, absence of associated arm swinging when walking.

The symptoms of the disease develop insidiously. Tremor, stiffness, or clumsiness in one of the limbs usually appears first; less often, the disease initially manifests as a gait change or generalized stiffness.

At the onset of the disease, attention is often drawn not so much to movement restriction as to pain and tension in the muscles of the limbs or back (one of the frequent misdiagnoses in patients with initial manifestations of Parkinson's disease is scapulohumeral periarthritis).

Initially, symptoms occur only on one side of the body, but gradually become bilateral over time. Movements become increasingly slower, and facial expression weakens. Due to infrequent blinking, the gaze appears piercing. Associated movements disappear (e.g., arm movements when walking). Fine finger movements become difficult (e.g., buttoning clothes, threading a needle, searching for keys in a pocket, playing musical instruments). Handwriting becomes smaller and less legible. The patient finds it increasingly difficult to change posture, e.g., get out of a chair or turn from side to side in bed. Speech becomes muffled and monotonous, sometimes stuttering. Gait changes: steps become shorter and shuffling. On the affected side, the patient is forced to drag the leg. Due to the predominance of flexor muscle tone, the patient's head and trunk lean forward, arms are bent at the elbows and pressed against the trunk, legs are bent at the knees ("pleader's posture").

Tremor usually occurs at rest, for example, in a hand resting calmly on the knee, or a leg when the patient is sitting and not bearing weight on it. In addition to the limbs, tremor often involves the lower jaw and lips, but extremely rarely the entire head. Movements of the thumb and index finger in parkinsonism tremor resemble "pill-rolling" or "counting coins".

Tremor is an extremely dynamic symptom and depends both on the patient's emotional state and movements. For example, hand tremor decreases or disappears during movement, but increases during movements of the other hand or legs (including when walking). Tremor usually greatly distresses patients because, in their view, it draws the attention of others and "gives away" their disease. However, unlike hypokinesia and rigidity, typical resting tremor practically does not hinder their motor activity, since it weakens or even completely disappears during movement. Only in some patients does it persist during movements and can cause difficulty.

The condition can fluctuate significantly during the day or from day to day, often depending on psycho-emotional and, possibly, external (weather) factors. Due to shyness and awkwardness felt by the patient in the presence of strangers (e.g., in public transport) and anxiety, stiffness and tremor may increase. Conversely, when among family, good friends, or when engaged in a favorite activity, motor activity is significantly facilitated. For example, musicians suffering from Parkinson's disease note that their condition improves after the conductor's baton taps on the music stand before the performance begins. According to the famous literary critic and master of artistic narrative I.L. Andronikov, known for his oral stories and also suffering from Parkinson's disease, his symptoms suddenly diminished as soon as he stepped under the stage spotlights.

2. Why does Parkinson's disease occur?

In recent years, it has become known that the cause of pathology in substantia nigra cells is the excessive accumulation of the alpha-synuclein protein due to its increased production (in a small number of genetically determined cases of the disease) or impaired degradation. Alpha-synuclein deposits in cells form intracellular Lewy bodies, which serve as one of the most important pathomorphological markers of the disease, detected only post-mortem.

In approximately 5–10% of cases, Parkinson's disease is familial, indicating that it may be based on a genetic defect manifesting in adulthood, although it has been identified in only a very small number of cases so far. It is hypothesized that cases of the disease occurring in the absence of a family history (i.e., relatives suffering from the same disease) are caused by a yet-unidentified external factor that exerts its effect in individuals with a genetic predisposition.

Hereditary predisposition may consist of the inadequacy of systems that prevent the accumulation of alpha-synuclein and other intracellular proteins in nerve cells or their damage during oxidative processes.

It has been noted that the disease is more common in non-smokers, although it remains unclear whether this fact is explained by a protective role of smoking or by the circumstance that individuals with a predisposition to Parkinson's disease are less active in developing this undoubtedly harmful habit. The disease often manifests after psycho-emotional stress, but its role has not been definitively determined.

3. Motor symptoms of Parkinson's disease

The primary clinical manifestation of Parkinson's disease is parkinsonism syndrome, which has the following features:

• bradykinesia (slowness of all movements);

• impaired fine motor skills of the limbs;

• fatiguability of rapid alternating movements of the hands and feet;

• muscle stiffness (increased tone) (muscle rigidity);

• tremor of the hands and feet, which is most pronounced at rest;

• instability when getting up, turning, or changing the motor program;

• postural changes (most commonly stooped or hunchbacked posture, sometimes tilting of the trunk to one side);

• shortened stride length and shuffling gait, lack of associated arm swing when walking.

The symptoms of the disease develop insidiously and progress gradually. Initially, tremor, stiffness, or clumsiness typically appear in one of the limbs; less commonly, the disease initially manifests as a gait disturbance or generalized stiffness (such an onset is characteristic of the akinetic-rigid form).

At the onset of the disease, patients may experience pain and tension in the muscles of the limbs or back (one of the frequent misdiagnoses in patients with early manifestations of Parkinson's disease is humeroscapular periarthritis).

Initially, symptoms occur on only one side of the body, but over time they gradually become bilateral. Movements become increasingly slow, and facial expressions diminish (hypomimia). Due to infrequent blinking, the gaze appears piercing and sharp. Associated arm movements during walking disappear. Fine motor impairments emerge (manifesting, for example, when buttoning clothes, threading a needle, searching for keys in a pocket, or playing musical instruments). Handwriting becomes smaller and less legible. The patient finds it increasingly difficult to change posture, such as getting up out of a chair or turning from side to side in bed. Speech becomes muffled and monotonous, sometimes stuttering. The gait changes: steps become shorter, shuffling, and festinating. Due to the predominance of flexor muscle tone, the patient's head and trunk are tilted forward, the arms are bent at the elbows and pressed against the torso, and the legs are bent at the knees ("pleader's posture").

Tremor typically occurs at rest, for example, in a hand resting calmly on the knee, or in a leg when the patient is sitting without weight-bearing. In addition to the limbs, tremor frequently involves the lower jaw and lips, but extremely rarely the entire head. The movements of the thumb and index finger in parkinsonian tremor resemble "pill-rolling" or "counting coins." Tremor is an extremely dynamic symptom and depends both on the patient's emotional state and on their movements. For example, hand tremor decreases or disappears during movement, but intensifies with movements of the other hand or legs (including during walking). Tremor is usually very distressing to patients because, in their view, it draws the attention of others and "gives away" their illness. However, unlike hypokinesia and rigidity, typical resting tremor practically does not hinder their motor activity, since it diminishes or even completely disappears during movement. Only in a subset of patients does it persist during movement and cause functional difficulty.

The condition can fluctuate significantly throughout the day or from day to day, often depending on psycho-emotional and possibly external (weather) factors. Due to shyness, anxiety, and embarrassment experienced by the patient in the presence of strangers (e.g., in public transport), stiffness and tremor may worsen. Conversely, when staying among family and close friends, or engaging in a favorite hobby, motor activity is significantly facilitated. For example, musicians suffering from Parkinson's disease note that their condition improves after the conductor's baton taps the music stand before a performance begins. According to the famous literary scholar and master of artistic storytelling I.L. Andronikov, known for his oral stories and also suffering from Parkinson's disease, his symptoms would suddenly subside as soon as he stepped under the stage spotlights. In addition to the aforementioned movement disorders, Parkinson's disease causes "non-motor" symptoms originating from internal organs: intestinal motility slows down, leading to constipation, whereas the bladder becomes disinhibited, resulting in more frequent urination, primarily at night. When standing up or remaining in an upright position for a prolonged period, and sometimes after eating, blood pressure may drop, accompanied by a feeling of sudden weakness or dizziness.

Concentration during intellectual work can be very difficult. Extra effort is required to recall the right word, which is sometimes right on the tip of the tongue but refuses to "surface." Salivation increases, including at night—patients often notice wet spots on the pillow even at the onset of the disease.

The person often becomes more anxious and irritable. Prolonged periods of depressed mood—depression—frequently occur. This is due to two reasons: first, the patient is distressed by the inability to function as fully as before, either at work or at home; second, the activity of the brain regions responsible for maintaining a balanced mood is impaired. The manifestations of depression are diverse and include not only a low mood, but also unusual fatigue, increased irritability or apathy toward surroundings, and changes in appetite. Difficulties arise in interpersonal relationships. This primarily concerns family dynamics. Patients may be dissatisfied with both themselves and those around them. If both the patient and their loved ones are aware of these psychological manifestations of the disease, this alone helps alleviate psychological tension and foster harmonious relationships.

4. Non-motor symptoms of Parkinson's disease

Parkinson's disease is characterized not only by movement disorders (motor symptoms), but also by so-called non-motor symptoms, which encompass a wide range of disturbances. Non-motor symptoms in Parkinson's disease include psychiatric (cognitive, affective, behavioral), autonomic, sensory, and other disorders.

The occurrence of non-motor symptoms in this disease is due to the fact that, in addition to the degeneration of the substantia nigra, neurons are damaged in other parts of the brain. A number of symptoms, such as constipation, anxiety, depression, sleep disorders, olfactory dysfunction, urinary frequency, and sexual dysfunction, are among the earliest manifestations of the disease, appearing several years or even decades before motor disorders. This is because the involvement of brain regions controlling these processes occurs at an earlier stage of disease development.

It should be noted that all the symptoms listed below may occur in various combinations in different patients, reflecting the course of the disease. These disorders are described to provide an understanding of what abnormalities can occur in Parkinson's disease. If you or your relative experience similar disturbances, it is likely that they are also symptoms of this condition. Information about the presence of non-motor symptoms will enable the attending physician to better tailor therapy and improve the patient's condition.

Sleep and wakefulness disorders

As early as James Parkinson in his "Essay on the Shaking Palsy," it was written: "Sleep is greatly disturbed. The trembling of the limbs continues during sleep, and increases until it awakens the patient… and finally, constant sleepiness and even slight confusion are observed." According to modern data, sleep and wakefulness disorders are the second most common non-motor symptom of Parkinson's disease and are observed in 60–90% of patients.

Chronic insomnia is the most frequent sleep disorder in patients with Parkinson's disease. Sleep onset insomnia occurs in every third patient with Parkinson's disease and is most often associated with the worsening of parkinsonian symptoms at night or the administration of antiparkinsonian medications in the evening. In some patients, sleep onset difficulties at night are triggered by disorders such as anxiety and depression, circadian rhythm disruption, and restless legs syndrome.

Sleep maintenance insomnia with frequent nocturnal awakenings is observed in almost many patients. Normally, a healthy person changes posture during sleep every 20 minutes. Because hypokinesia can worsen in the evening and at night, patients become unable to change posture regularly, leading to increasing discomfort and awakening. The causes of nocturnal awakenings can also include increased muscle rigidity and tremor, muscle cramps and limb pain, snoring, and other sleep-related breathing disorders. A feeling of restlessness may also occur, prompting movements, most frequently in the legs. Frequent nighttime urination can also lead to awakenings, after which it can be difficult to fall back asleep.

If early morning awakening occurs, it is usually caused by depression, evening alcohol or sedative intake, circadian rhythm disorders (so-called "larks"), as well as the intensification of motor symptoms against the background of a waning evening dose of dopa drugs and their derivatives.

Another sleep disorder characteristic of Parkinson's disease is REM sleep behavior disorder. As the name implies, this sleep disorder occurs specifically during the rapid eye movement (REM) phase of sleep, when a person dreams. In REM sleep behavior disorder, vivid, unusual, and frightening dreams occur. A distinctive feature of this disorder is that the patient suffering from it begins to enact the dreams they are experiencing. As a result, the patient may thrash their arms during sleep, make leg movements as if running or riding a bicycle, and may also shout. This disorder occurs in approximately 20–50% of Parkinson's disease cases. REM sleep behavior disorder can pose a danger to the patient or their relatives if they make overly active movements during sleep that could lead to injury or falling out of bed.

Nocturnal myoclonus (sleep starts) refers to brief muscle twitches. Nocturnal myoclonus typically occurs during the course of long-standing disease. It is hypothesized that nocturnal myoclonus is associated with increased serotonergic transmission in the brain, which may occur under the influence of dopa drugs and their derivatives.

Restless legs syndrome is a disorder characterized by unpleasant sensations in the lower extremities that appear at rest, compel the patient to make movements to relieve them, and frequently lead to sleep disturbance. Complaints characteristic of restless legs syndrome are found in approximately a quarter of patients. This disorder can also occur in healthy individuals and is associated with dopamine deficiency in the brain. However, some patients experience sensations in the legs similar to restless legs syndrome that may be due to other causes. Notably, conditions that can mimic restless legs syndrome include: worsening of motor symptoms due to the end-of-dose effect of antiparkinsonian medications, leg muscle cramps, impaired venous outflow, and pain associated with polyneuropathy (a condition affecting limb nerves, occurring in diabetes mellitus and other diseases). It is important to distinguish true restless legs syndrome from its "mimics" in order to select appropriate treatment for the patient. In true restless legs syndrome, unpleasant sensations in the legs occur in the evening and at night, leading to insomnia; they are intensified at rest and alleviated by limb movement.

Restless legs syndrome is frequently accompanied by periodic limb movement disorder. This refers to a condition where periodically repeating movements occur during sleep, predominantly involving the lower extremities and characterized by extension of the big toe, dorsiflexion of the ankle, and flexion of the leg at the knee joint. Unlike myoclonus, periodic limb movements last longer (up to 5 seconds), are often unilateral, and repeat rhythmically every 20 to 40 seconds. Pronounced periodic limb movements can cause frequent nocturnal awakenings.

Daytime sleepiness is one of the characteristic non-motor symptoms of Parkinson's disease, observed to varying degrees in approximately half of patients. It may present as persistent sleepiness occurring at any time of day—more frequently in the afternoon—lasting for several hours, or as paroxysmal episodes of falling asleep. In some patients, falling asleep can occur suddenly, even without preceding sleepiness. This particular form of daytime sleepiness carries danger, as the patient may fall asleep "without warning" while at work or driving. Daytime sleepiness is often related to dysfunction of the wakefulness-promoting system in Parkinson's disease, but it can also be a consequence of certain medications or nocturnal sleep disturbances. Antiparkinsonian medications, especially dopamine receptor agonists such as ropinirole, pramipexole**, and piribedil**, can also lead to the development of daytime sleepiness. If you or your relative develops pronounced daytime sleepiness or sudden sleep attacks after starting these medications or increasing their dose, you must consult a physician. Daytime sleepiness most frequently causes concern in patients who lead an active lifestyle, continue to work, and drive automobiles. If daytime sleepiness occurs, we recommend refraining from driving until the cause of the sleepiness is identified and resolved.

Apnea syndrome is a condition characterized by episodes of marked narrowing or closure of the upper airway lumen during sleep, accompanied by temporary cessation of breathing and a decrease in blood oxygen saturation. Such breathing cessations can occur up to 15–30 times or more per hour, though their duration usually does not exceed one minute. During an apnea episode, brain activation occurs, causing the person to wake up, the airway to open, and breathing to resume. Since these awakenings are very brief, they are not remembered, but complaints may include snoring, a sensation of choking during sleep, poor morning well-being after waking, headaches, and daytime sleepiness. Men suffer from apnea syndrome more often than women. Individuals with excess weight and a large neck circumference are also prone to developing this condition. Apnea syndrome frequently coexists with hypertension, diabetes mellitus, and cardiovascular diseases. Apnea syndrome affects more than 20% of the population over 60 years of age, although in Parkinson's disease it may occur even less frequently due to lower patient body weight. Identifying this disorder may require consultation with a sleep specialist (somnologist) and special diagnostic tests (pulse oximetry, cardiorespiratory monitoring, polysomnography).

Circadian rhythms (from Latin *circa* "about, around" + *dies* "day") are cyclic fluctuations in the intensity of various biological processes associated with the alternation of day and night. The period of circadian rhythms is usually close to 24 hours. Melatonin is one of the links in the regulation of circadian rhythms: during the day, light striking the retina activates its photosensitive cells, and information from them is transmitted to the structures where melatonin is produced. Sunlight suppresses melatonin production, which is why during the daytime a person does not feel sleepy and can actively engage in activities. When sunlight stops reaching the retina, melatonin production begins, which "prepares" the body for sleep. With aging, cyclic melatonin production is disrupted due to changes in the brain structures that produce it, clouding of the lens, and reduced time spent outdoors. In Parkinson's disease, these changes can be more pronounced, which is why patients more frequently experience circadian rhythm disturbances in the form of a phase shift of sleep to an earlier time ("larks") or a later time ("owls"). When circadian rhythms shift in one direction or the other or become less organized, daytime sleepiness and nighttime insomnia can occur.

Autonomic disorders

The autonomic nervous system regulates bodily functions such as gastric and intestinal motility, blood pressure and heart rate regulation, respiration, urination, skin condition, and so on. In Parkinson's disease, dysfunctions may be observed in the cardiovascular, digestive, and urogenital systems—including sexual dysfunction—as well as disorders of sweating and salivation. This section will describe the most common and significant autonomic nervous system disturbances.

Orthostatic hypotension (from Greek *orthos* meaning "straight" + *stasis* meaning "standing") is a decrease in blood pressure that occurs after changing from a horizontal to a vertical position. It manifests as darkening before the eyes, dizziness, generalized weakness, presyncope, drowsiness, fainting, and unsteadiness when walking. Sometimes orthostatic hypotension can remain asymptomatic for a long time. When a person stands up, most of the blood pools in the lower extremities, which leads to a decrease in blood flow volume in the upper body and the brain, potentially impairing its function due to oxygen deprivation. However, this does not normally happen because the heart starts beating faster and more actively, pumping out more blood to the brain. In Parkinson's disease, this mechanism can be impaired, so the pooling of most of the blood in the lower extremities upon standing is not accompanied by a physiological increase in heart rate, leading to a drop in blood pressure and the appearance of symptoms of inadequate oxygen supply to the brain. To identify this disorder, the physician asks the patient to keep a special blood pressure diary, taking two consecutive blood pressure measurements: while lying down and after 3 minutes in a standing position. A drop in systolic pressure of more than 20 mm Hg or in diastolic pressure of more than 10 mm Hg within 3 minutes after transitioning from a horizontal to a vertical position confirms the presence of orthostatic hypotension.

Triggering factors and prevention strategy for orthostatic hypotension in patients with Parkinson's disease

In patients with Parkinson's disease, orthostatic hypotension can occur both as a result of the disease itself and due to other causes, including drug side effects, alcohol consumption, and overheating. Risk factors for developing orthostatic hypotension also include: older age, female sex, hypertension, tachycardia, diabetes mellitus, low body weight, and smoking. In most patients, orthostatic hypotension is combined with supine hypertension (elevated blood pressure in the horizontal position). The cause of this phenomenon is not yet fully understood. It must be remembered that hypertension can be a side effect of drugs used to treat orthostatic hypotension. The combination of orthostatic hypotension and persistent or nocturnal hypertension presents a clinical dilemma because the clinician must choose between persistent blood pressure elevation and the risk of falls caused by a sharp drop in blood pressure.

Postprandial hypotension is characterized by the same clinical manifestations as orthostatic hypotension. However, patients often fail to notice the connection between food intake and the development of hypotensive symptoms because they may occur with a delay. The maximum blood pressure drop is observed within 35 minutes to 1 hour after eating, but hypotension can also occur 2 hours later.

Gastrointestinal disorders may be observed even before the onset of motor symptoms of the disease. Gastrointestinal dysfunction includes: hypersalivation, dysphagia, nausea and vomiting, and constipation.

Urinary disorders manifest as frequent and sudden strong urges to urinate that force the patient to rush to the restroom immediately; sometimes such urges can lead to urinary incontinence. Urinary retention, erectile dysfunction, and ejaculatory disorders may also occur.

Trophic skin disorders are observed in approximately half of patients and include impaired sweating: excessive sweating or, conversely, dry skin, as well as decreased or increased sebum production.

Impaired pupillary light reflex can lead to impaired vision in the dark and discomfort in the eyes under bright light.

5. How the diagnosis is made

Parkinson's disease is highly variable in its manifestations, so establishing a diagnosis is often a challenging task that only an experienced specialist can handle. The disease develops insidiously and progresses slowly, so in the earliest stages symptoms may not be noticeable. However, there are certain criteria that allow for the diagnosis of this disease.

The criteria include:

• Hypokinesia – slowness of movement,
• Rigidity – increased muscle tone,
• Rest tremor – trembling of the limbs in a relaxed state.

Making a diagnosis requires the presence of hypokinesia combined with either rigidity or rest tremor. Most frequently, however, all three symptoms are present. If the disease is in an early stage, confirmation of the diagnosis may take several months until clinical symptoms become more pronounced. An assessment of disease progression and treatment efficacy also helps in diagnosing Parkinson's disease.

Traditional supplementary diagnostic methods, both laboratory and instrumental, do not reveal specific changes in Parkinson's disease and are mainly used to rule out other diseases.

Given the difficulty of diagnosing Parkinson's disease, especially in the absence of sufficient clinical experience, the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease have been developed. These criteria take into account the entire spectrum of symptoms characteristic of and indicative of Parkinson's disease, as well as those whose presence points to a different disease.

6. Diseases resembling Parkinson's disease

Approximately 10–15% of parkinsonism cases are caused not by Parkinson's disease, but by other neurodegenerative brain disorders. These diseases are characterized by more extensive nervous system involvement not limited to the substantia nigra, and therefore they manifest as a combination of parkinsonism with other symptoms ("parkinsonism-plus syndromes"). Multiple system atrophy and progressive supranuclear palsy are particularly common within this group.

In addition to parkinsonism, multiple system atrophy is characterized by the early development of severe autonomic failure, expressed as a sharp drop in blood pressure after eating, especially after breakfast (postprandial hypotension), which manifests as weakness, drowsiness after breakfast, a desire to lie down and take a nap, and the inability to maintain blood pressure in a vertical position (orthostatic hypotension), which the patient perceives as non-vestibular dizziness, a feeling of instability and weakness, as well as urgent urges to urinate that require very prompt voiding and can subsequently lead to urinary incontinence. Some patients with multiple system atrophy develop leg edema. Sometimes the leading motor syndrome is not parkinsonism, but impaired motor coordination due to the degeneration of cerebellar structures. Patients develop early speech disturbances; speech becomes slurred, high-pitched, or variable in amplitude. Sleep-related vocalization and agitation involving flailing of arms and legs, or running movements, are also very characteristic and early symptoms of multiple system atrophy.

In progressive supranuclear palsy, alongside parkinsonism, balance disorders develop early; patients report frequent falls (typically falling backward), eye movement disorders, speech disorders (the voice becomes very low and coarse with a metallic timbre), and swallowing problems. One of the key features of "parkinsonism-plus" or atypical parkinsonism, as it is also called, is the lack of effect or insufficient effect from antiparkinsonian therapy. On lateral brain MRI scans in progressive supranuclear palsy, midbrain atrophy or the "hummingbird" sign is often (but not always!) detected, as the brainstem with an atrophic midbrain resembles a hummingbird with a thin, long beak.

In dementia with Lewy bodies, the parkinsonism syndrome is preceded by (or develops concurrently with) cognitive impairments (disorders of attention, thinking, and visuospatial functions) that rapidly reach the stage of dementia. Patients develop psychotic disorders very early (sometimes before starting antiparkinsonian drugs or shortly after their prescription) in the form of visual hallucinations, unusual sensations of someone being in the room, or the feeling of a "shadow" passing by. Patients often report "seeing" a cat or other small animals, and sometimes certain people or dwarfs. In addition, dementia with Lewy bodies very frequently presents with pronounced autonomic disorders (orthostatic or postprandial hypotension, frequent urination—initially at night and later during the day, and urinary incontinence).

Occasionally, parkinsonism is caused by intoxications (e.g., carbon monoxide, manganese, cyanide, or methyl alcohol poisoning) or traumatic brain injury. Postencephalitic parkinsonism, which was widespread in the past and had an infectious origin, has been diagnosed extremely rarely in recent decades.

Computed tomography or magnetic resonance imaging of the brain makes it possible to diagnose vascular brain lesions, hydrocephalus, or tumors, which are also sometimes the cause of parkinsonism.

For many years, vascular parkinsonism, arising as a complication of strokes or dyscirculatory encephalopathy, was misdiagnosed in many patients with Parkinson's disease. In fact, vascular parkinsonism is quite rare (accounting for no more than 5–6% of parkinsonism cases); however, its diagnosis is very crucial because it requires a special treatment approach. Diagnosing vascular parkinsonism requires a specific clinical picture, which generally differs from the symptoms of Parkinson's disease. For example, in vascular parkinsonism, tremor is rare, symptoms predominate in the legs, excitation symptoms during sleep (somniloquy, arm flailing, etc.) are absent, and there is an insufficient effect from dopa drugs and its derivatives. On brain MRI for the diagnosis of vascular parkinsonism, clear changes in the structures responsible for the development of parkinsonism (substantia nigra of the midbrain, thalamus, putamen) must be present. Without these signs, the diagnosis of vascular parkinsonism is unreliable.

In patients with parkinsonism, it is also important to rule out potential drug-induced causes. Drug-induced parkinsonism is usually caused by antipsychotic agents (such as chlorpromazine**, haloperidol**, trifluoperazine**, sulpiride**, thioridazine**, etc.), which are particularly frequently used in psychiatric practice, but can also be caused by metoclopramide (used to treat nausea, vomiting, and other gastrointestinal disorders), cinnarizine (used to improve cerebral circulation), or antihypertensive drugs containing reserpine. In drug-induced parkinsonism, symptoms disappear within 4–8 weeks after drug withdrawal in the majority of cases, but recovery is sometimes delayed for several months or even years.

Parkinsonism is frequently misdiagnosed in patients with essential tremor. Essential tremor (benign familial tremor) is a disease whose main symptom is tremor, which manifests not at rest (unlike parkinsonian tremor), but during movement (e.g., when writing, bringing a spoon to the mouth, or pouring water into a glass). Unlike Parkinson's disease, essential tremor is observed in both hands from the very beginning, and patients often develop head tremor. Essential tremor is 2–4 times more common than parkinsonism, often occurs at a younger age, progresses very slowly, and does not require treatment in mild and moderate cases. Approximately half of patients with essential tremor have relatives suffering from the same condition.

7. Treatment of Parkinson's disease

Maintaining motor functions depends on two main components: successful drug therapy and adequate physical activity.

All treatment must be carried out under the supervision of your physician, who will evaluate its efficacy and safety. Unfortunately, all drugs have side effects, and some of them make a particular drug undesirable or contraindicated specifically for you. The entire possible spectrum of side effects is reflected in the package leaflet of the drug.

Reading this list plunges some patients into a "stupor"; however, it must be understood that truly dangerous drugs are not approved for clinical practice, and most of the side effects listed in the leaflet are extremely rare. In any case, the benefit you derive from taking the drug is generally orders of magnitude greater than the hazard posed by side effects. Of course, there are exceptions to this rule, which are well known to the physicians prescribing a particular drug to you. Nevertheless, if reviewing the leaflet causes you to doubt the safety of this drug for you, consult your physician.

Antiparkinsonian drugs that can be taken once a day are currently available, making treatment more convenient. However, you will have to take many agents several times a day, and given the need to take multiple medications at once, the treatment regimen can be quite complex.

To avoid forgetting to take each of the medications at its designated time (and this is very important for treatment success), we recommend purchasing a special plastic compartmentalized pillbox or simply using empty medicine bottles. Depending on how frequently the physician has prescribed the medication for you throughout the day, you write on each bottle, for example: "morning," "day," "evening," or "8, 12, 16, 20 hours." You or your family members place the medications into these bottles the evening before, thereby virtually eliminating incorrect medication administration. Modern smartphones, tablets, and other electronic devices can be programmed to remind you to take your medications at the right time.

In some patients, antiparkinsonian drugs cause nausea and sometimes vomiting. As a rule, nausea and vomiting are caused not by stomach irritation, as many patients believe, but by the stimulation of a specific brain area—the so-called "vomiting center," which contains dopamine receptors. Within 2 weeks, the receptors of the vomiting center usually adapt to the dopaminergic agent you are taking, and the sensation of nausea subsides. To reduce nausea during the initial treatment period or after a significant dosage increase, the medication should be taken during or immediately after meals. Subsequently, certain drugs (primarily levodopa) should be taken on an empty stomach—when taken this way, their effect is enhanced, sets in faster, and lasts longer. If nausea prevents you from taking the prescribed medication, your physician will recommend taking domperidone for 2–3 weeks, which will block the receptors of the vomiting center without exacerbating parkinsonism symptoms.

Like nausea, other drug side effects should not be feared, as they can all be resolved by adjusting the dosage or changing the medication under your attending physician's guidance.

One of the universal techniques employed by physicians to reduce the risk of side effects is dose titration: initially, a given drug is prescribed at the lowest possible dose, and then the dose is gradually increased over several weeks to an effective level, provided the drug is well tolerated. At the same time, efforts are made to limit the drug dose, aiming not for complete elimination of symptoms, but for sufficient functional improvement to allow the patient to continue working or maintain independence in daily life.

8. Side effects appearing with long-term use of dopa drugs and their derivatives

For over 50 years, levodopa (L-DOPA, the levorotatory isomer of the amino acid dihydroxyphenylalanine) has remained the most effective treatment for Parkinson's disease. In terms of efficacy, it outperforms any other antiparkinsonian drug and even neurosurgical intervention. It provides the most reliable antiparkinsonian effect, producing improvement in virtually 100% of patients with Parkinson's disease. No patient with Parkinson's disease who strives to maximize their active lifestyle can avoid taking it. Levodopa is considered the "gold standard" for treating Parkinson's disease. It increases patients' life expectancy. To date, there is no convincing evidence of a neurotoxic effect of dopa preparations and their derivatives. Moreover, the ability of small doses of dopa preparations and their derivatives to exert a neuroprotective effect cannot be ruled out.

After oral administration, levodopa penetrates the brain and is converted there by functioning nerve cells into dopamine, replenishing its deficiency. Modern drugs contain a combination of dopa preparations and their derivatives with a DOPA decarboxylase enzyme inhibitor, which blocks the metabolism of dopa preparations and their derivatives in peripheral tissues. As a result, a larger portion of dopa preparations and their derivatives reaches the brain, and the likelihood of side effects associated with the peripheral action of the drug is reduced. In the early stages of Parkinson's disease, even small doses of dopa preparations and their derivatives often produce a significant effect, almost completely eliminating parkinsonian symptoms. Unfortunately, several years after starting levodopa therapy, the response to the drug changes in a significant number of patients: the duration of a single dose decreases, and involuntary movements (dyskinesias) appear. The patient takes the prescribed single dose of dopa preparations and their derivatives, and it begins to work after about 40 minutes—the patient enters the "on" period, characterized by a reduction in parkinsonian symptoms. However, after only 3 to 4 hours—and subsequently even faster, after just 2 to 2.5 hours—the drug's effect weakens, marking the "off" period with a decrease in motor activity. Sometimes the "on" and "off" states are accompanied by various types of involuntary movements. Freezing of gait also occurs during the day, when for a few seconds or minutes the patient cannot move from the spot. For patients with this disorder, turning around or walking through a relatively narrow doorway can be particularly difficult. Fluctuations in motor activity, which can range widely from excessive motor activity at peak dose to a sharp decline in motor capabilities during the "off" period, are referred to in medical literature as motor fluctuations.

Several types of motor fluctuations are distinguished. The "wearing-off" phenomenon (end-of-dose failure) is characterized by a gradual, predictable, partial return of parkinsonian symptoms towards the end of the duration of the previous dose of dopa preparations and their derivatives. As the effect of a single dose of dopa preparations and their derivatives wanes, many patients also note low mood, anxiety, sweating, palpitations, increased pain, etc. ("non-motor fluctuations").

Over time, the patient's transition from the "on" state to the "off" state becomes increasingly brief and abrupt, which is referred to as the "on-off" phenomenon.

Sometimes the "off" period occurs suddenly, regardless of the timing of medication intake. In addition to the aforementioned fluctuations, a delayed onset of the "on" state or a complete lack of an "on" response can occur, where taking a regular dose is not accompanied by an improvement in clinical symptoms or takes insufficiently fast.

During the "on" state (at the peak dose of dopa preparations and their derivatives), rapid, "dancing" (choreiform) movements may occur, predominantly involving the upper body ("peak-dose dyskinesia"). This acts as a limiter, requiring a reduction in dopaminergic therapy, since increasing the dose will lead to worsening dyskinesias. This phenomenon is based on dopamine receptor hypersensitivity. "Off"-period dystonia is a forceful, prolonged, often painful spasm of the lower limb muscles, frequently accompanied by plantar flexion or turning inward of the foot.

Since the risk of fluctuations and dyskinesias depends on the total cumulative dose of dopa preparations and their derivatives, they are usually prescribed only when there is a real decline in the patient's functional abilities that interferes with their occupational or daily living activities.

In younger patients (under 60 years old), fluctuations in the effect of dopa preparations and their derivatives develop more rapidly. Therefore, clinicians try to delay the initiation of dopa preparations and their derivatives in this age group, starting treatment with other antiparkinsonian medications. Only when these agents fail to provide the desired effect and adequate patient mobility are small doses of dopa preparations and their derivatives added. At the same time, some specialists believe that excessively delaying the prescription of dopa preparations and their derivatives is not an optimal management strategy, as it is frequently accompanied by inadequate symptom control. Meanwhile, adequate correction of motor functions is the primary key to better long-term treatment outcomes.

"Off" periods and dyskinesias can be agonizing for patients, and they may be tempted to relieve their condition by taking an extra dose of dopa preparations and their derivatives or another antiparkinsonian agent. Often, through a vicious cycle mechanism, this leads to an exacerbation of the patient's instability. Consequently, any changes to the treatment regimen, especially in the presence of fluctuations, must be coordinated with the attending physician. Managing fluctuations and dyskinesias is a complex task even for an experienced specialist and can only be successfully resolved through close collaboration between the doctor and the patient.

The goal of adjusting the treatment regimen is to maximize the duration of the "on" period in the absence or with minimal presence of dyskinesias. Keeping a daily activity diary in 1-hour intervals can help the specialist analyze the relationship between the "off" period and dyskinesias, as well as their occurrence relative to the timing of medication intake.

When the duration of action of dopa preparations and their derivatives decreases (the "wearing-off" phenomenon), most specialists initially resort to fractionating the dose of dopa preparations and their derivatives (reducing the single dose while shortening the interval between administrations) and switching from an immediate-release formulation to an extended-release formulation. In addition, the effect of dopa preparations and their derivatives can be enhanced by improving their absorption. To achieve this, the drug should be taken at least 60 minutes before meals and no earlier than 2 hours after eating. Furthermore, protein intake should be reduced throughout the day (amino acids resulting from dietary protein breakdown compete with levodopa for intestinal absorption).

Freezing episodes that develop during the "off" period respond to techniques that shorten the "off" phase. It is helpful to train the patient in strategies to overcome freezing by marching in place, performing unusual dance-like movements, stepping over an imaginary line drawn in the patient's path, or using a specialized cane with a small flip-down metal bar at the bottom, which the patient can step over to initiate movement.

Other recommendations for freezing episodes:

• stop trying to force movement;

• try shifting weight from one foot to the other;

• slightly bend your knees, lift your foot off the floor, and step forward;

• count "one, two, three" or give yourself the command "left-right, left-right";

• hum a rhythmic tune;

• visualize the sound of footsteps on pavement and lift your foot to take a step;

• try to mimic the gait of a person walking ahead of you;

• if you have trouble navigating a narrow space, try looking beyond it: visualize the place you will reach once you get through that space.

In cases where the transition from "on" to "off" becomes unpredictable, it may be possible to return to more frequent administration of relatively large doses of dopaminergic drugs ("dose staggering"). This will lead, on the one hand, to an increase in the "on" period during the daytime when the patient needs to be active; on the other hand, the "off" period will also increase, but will shift to the evening and become more predictable. Managing "on-off" fluctuations becomes more complicated when the "on" period is accompanied by dyskinesias. In such cases, there may be no unequivocally satisfactory solution, and the patient must decide whether to put up with hyperkinesias during the "on" state or suffer from a prolonged "off" period. Patients usually choose the former.

However, it is sometimes impossible to completely get rid of motor fluctuations. In this case, the only option is to adapt to them: you should do all your necessary tasks during the hours when you feel better, and spend the remaining hours on activities that do not require movement, such as reading, watching television, or listening to the radio.

In Russian clinical practice, Parkinson's disease patients are often prescribed drugs whose efficacy in this condition has not been convincingly proven. These are often so-called "vascular drugs", frequently administered via intravenous infusion. Their prescription is often justified by naive and archaic notions linking Parkinson's disease to "poor cerebral blood vessels", which in most patients, even of advanced age, are not significantly affected. Any positive experience with their use, if it exists at all, is explained by nothing other than a placebo effect.

The placebo effect is achieved through the patient's faith in the physician, incorrectly conveyed or misunderstood information, the power of tradition, and sometimes the patient's despair with classical medicine methods. Specialists treating Parkinson's disease are well aware that a significant proportion of patients respond well to placebos, but this effect is never permanent. Most importantly, ineffective drugs and other treatments should not interfere with adequate therapy for the disease, as delaying it can have adverse long-term consequences.

Overall, patients with Parkinson's disease should exercise caution when using any medications, some of which carry the risk of worsening their condition. This applies primarily to antipsychotic drugs. The same can be said for a number of drugs widely used in neurological and general practice that are capable of blocking dopamine receptors and exacerbating parkinsonian symptoms: cinnarizine (including combined preparations of cinnarizine and piracetam**), metoclopramide**, promethazine. Iron preparations prescribed for iron deficiency anemia can reduce the efficacy of dopaminergic drugs and often require an increase in their dosage.

Be cautious with drugs that cause a sedative effect, including sleeping pills, especially if they are long-acting (e.g., bromdihydrochlorphenylbenzodiazepine**). When using them, inform your attending physician about the severity of the sedative effect and any potential worsening of daytime symptoms. On the other hand, "nootropic" drugs such as piracetam** can cause agitation in some patients.

Finally, it should be borne in mind that during surgical interventions performed for concomitant conditions, general anesthetics are often used for anesthesia—drugs with a powerful sedative effect capable of inducing the artificial coma necessary for surgery. In elderly people, they can provoke confusion. Some surgical procedures can be performed under the influence of less hazardous drugs, and in certain conditions, surgery can be avoided. Ask your attending physician about alternative treatment options before choosing surgery.

The list of drugs capable of causing deterioration in Parkinson's disease patients is quite extensive, so it makes sense to consult a neurologist before starting regular use of a new medication, even if it was prescribed for a different condition.

Rapid progress in the study of the pathogenesis of Parkinson's disease, as well as the development of cutting-edge medical technologies (in particular, stem cell transplantation techniques capable of replacing dying cells, or gene therapy), provide hope that a way to significantly slow down the progression of this disease will be found in the coming decade.

10. Rules for a Doctor's Visit

To get the maximum benefit from your doctor's visit, try to follow these simple recommendations.

• Most doctors welcome it if you familiarize yourself with information regarding your disease. This will help you participate in treatment decisions and enable you to formulate your complaints more accurately.

• Make a list of questions for the doctor in advance.

• Do not delay visiting your supervising physician for long, especially if you feel deterioration or treatment complications.

• Bring all the medications you are currently taking to every visit.

• Do not take any additional remedies right before the doctor's visit—it is important for the doctor to see how your current treatment regimen is working.

• Be frank with your doctor during the visit.

• Do not be afraid to ask questions and discuss symptoms with your doctor that, in your view, are unrelated to Parkinson's disease.

• Write down the answers to your questions and the doctor's recommendations so you don't forget them.

• It is important to understand that you are not alone with your disease: there are many specialists who can help you.

11. Neurosurgical Treatment

Neurosurgical treatment is currently performed for two main indications:

• severe, disabling fluctuations and dyskinesias that do not improve with optimal medical therapy;

• pronounced tremor resistant to medications.

The following neurosurgical options are possible for Parkinson's disease:

• Deep brain stimulation
• Stereotactic thalamotomy and pallidotomy
• Focused ultrasound thalamotomy

Deep brain stimulation is considered worldwide as a highly effective treatment method for advanced and late stages of Parkinson's disease. The main targets used for movement disorders are the subthalamic nucleus, the internal segment of the globus pallidus, and the thalamic nuclei.

Neurostimulation is carried out using autonomous implantable systems and provides a non-destructive, reversible alteration of brain structure activity. After electrodes are implanted into the brain tissue, their ends are routed subcutaneously to the neck area, where they are connected to an impulse generator. A handheld remote control—a programmer—is used to manage stimulation parameters. During the surgical procedure, the patient remains conscious. It is important for the surgeon to maintain contact with the patient in order to discuss their sensations. The brain itself has no pain receptors and, accordingly, the patient feels no pain. The duration of the surgery is several hours. Most patients continue anti-parkinsonian therapy after such an intervention, but its dosage is reduced.

Numerous studies have confirmed that deep brain stimulation has a good safety profile, especially in individuals under 75 years of age. However, like any other surgical intervention, this procedure is accompanied by a certain percentage of complications, which is minimal when performed by an experienced surgical team. The efficacy of neurostimulation is determined by three main factors: 1) patient selection for surgical treatment; 2) precise electrode implantation into the chosen target; 3) an individualized electrical stimulation program and adapted pharmacotherapy.

During destructive stereotactic surgeries, a specific brain structure responsible for a particular disease symptom is destroyed, leading to a reduction in symptoms. Thalamotomy is used to reduce unilateral tremor. The indication for pallidotomy is the appearance of unilateral dyskinesias on the contralateral side.

Focused ultrasound is a modern, minimally invasive medical technology used for ultrasonic thermal destruction of brain tissue without incisions in soft tissues or skull bones. More than 1,000 ultrasound beams are focused at a precisely targeted point within the brain tissue, such as the basal ganglia, creating thermal destruction there. Throughout the procedure, the patient remains conscious, and MR thermography is recorded using a 3-Tesla MRI scanner. This allows for continuous neuroimaging and clinical feedback with the patient. The procedure itself takes about 3–4 hours, and the maximum effect develops after 2–3 months.

Currently, this method is used in Parkinson's disease only for therapy-resistant tremor. Focused ultrasound technology has application limitations; in particular, it is not suitable for patients with high bone density, which impedes the passage of ultrasound through the skull bones.

The main advantage of this method is the absence of surgical intervention and all resulting consequences: no risk of infection, no implants, no need for programming, and no constant patient anxiety about whether the stimulator is working properly. All of this significantly shortens the hospital stay and facilitates the overall postoperative recovery period.

The main disadvantage of focused ultrasound, like other ablative surgeries, is the irreversibility of its effect, which, when applied bilaterally to target structures in the brain, is associated with a high risk of gait and speech disturbances. Therefore, the procedure is performed on one side only.

Focused ultrasound is an alternative to traditional neurosurgical treatment, as it can be used in patients for whom surgery is contraindicated due to cardiovascular diseases or blood clotting disorders.

How to learn to live with Parkinson's disease

1. Your attitude towards the diagnosis

When an experienced neurologist concludes that you have Parkinson's disease, neither you nor your loved ones should despair. Of course, this disease cannot yet be radically cured. It inevitably limits your activity both at work and at home. It requires continuous treatment, including the ongoing intake of medications. But nowadays, with many different antiparkinsonian drugs available, it is possible to control its symptoms. Timely and well-chosen treatment can preserve your professional and everyday activity for many years.

To help you choose the right course of action, we can offer you the following tips.

• Choose a doctor whom you consider to be the best and trust them implicitly. Follow all the doctor's instructions regarding treatment. If you have any questions about the treatment, you should consult your doctor on how to proceed. Nowadays, in almost every region of our country, there are doctors specializing in the treatment of your disease who can always provide the necessary advice.
• Under no circumstances should you self-medicate! Make it a rule to use only the treatment prescribed or approved by your doctor. You can always discuss various treatment options with your doctor and jointly determine the treatment strategy.
• Organize your work and set up interaction with your loved ones so that you feel as confident and independent as possible. Think about what you can do in the new conditions when the disease has limited your usual motor activity, and what can help you unlock your potential. Learn to react calmly to the inappropriate curiosity of others.
• Communicating with people who have the same problems as you will help you cope with difficulties. Try not to give in to difficulties and overcome them.
• Establish a daily routine that takes your condition into account and stick to it regularly. Your peak activity level should coincide with the time you feel best, which is usually the first half of the day. In the evening, allow yourself to relax and rest.
• Sufficient and high-quality sleep is very important, so try to sleep at least 7–8 hours a night. It is best to go to bed and get up in the morning at the same time.
• Perform the recommended set of physical exercises. Try not to reduce, but rather to expand your motor activity. This will not only maintain your physical capabilities, but, as scientific studies show, may also slow down the progression of the disease.

2. Everyday activity

Everyday activity is understood as any form of human activity during the day. It includes work-related activities, any kind of housework, various forms of social activity, exploring areas of art and public events that interest you, and, of course, family and other interpersonal relationships at work and at home.

The word "activity" implies that all daily activities are carried out by you of your own free will, according to a plan you set for yourself, but in accordance with your real capabilities.

There are no identical patients, identical disease manifestations, and identical physical capabilities. One person falls ill while still of working age and continues to work, while another falls ill at an older age and may have other diseases besides Parkinson's disease that require treatment. Accordingly, the volume of everyday activity varies among different patients. Working patients have more of it, while elderly non-working patients have less.

Elderly patients are in greater need of advice and psychological support, so our advice is addressed primarily to elderly patients who are resisting the difficulties of a chronic disease and to their relatives who help overcome these difficulties. To present advice and recommendations on how best to organize everyday activity and overcome potential difficulties, it is most convenient to mentally trace your entire day from morning to evening.

You woke up

You took your last dose of medication yesterday evening, and by morning the effect of the medication has worn off, making it difficult for you to move. Therefore, your morning dose of medication and a glass of water to wash it down should be prepared from the evening on your bedside table or nightstand. To take the medication, you need to sit up. If you are lying on your back, bend your knees, press your feet against the mattress, lift your pelvis, and turn to the side of the bed where you intend to sit up. Then lower your legs off the bed while simultaneously supporting yourself with your arm, and sit on the edge of the bed. In a sitting position, it will be easy for you to take your medications.

Your medications may not take effect immediately. Therefore, if you are not sure that your strength has returned, do not rush to get up. Sit for a while and wait for the medications to start working. You can begin putting on your homewear while still sitting. Clothing should be simple, lightweight, fastening with large buttons or a zipper, or perhaps without any fasteners at all.

Put on your house slippers. It is better if they have rubber soles. To prevent the slippers from slipping off your foot, they should have a "back" (heel counter). Such slippers are easier to put on by using the pull tab.

You are getting out of bed

You are already dressed. The medication is starting to take effect. You can get up.

A healthy person has no problems with this because their arms, legs, and torso automatically move in coordination, and a healthy person doesn't think about how to make movements—they simply got up and walked.

In Parkinson's disease, coordination and automaticity of movements are reduced, so the patient has to think about how to perform certain movements.

To get out of bed, you need to move your feet backward under the edge of the bed. Your feet should be placed "shoulder-width apart." Then you bend your torso forward, place your palms on your knees, and, pushing off with your hands on your knees, smoothly stand up. By the way, you can get up from a chair in the exact same way.

Morning toilet and hygiene

Having gotten out of bed, you head to the restroom. If you recently have not been able to achieve confident walking and reliable balance immediately after your morning dose of medication, then along your path to the restroom (as well as on the way to other rooms), brackets (similar to door handles) or handrails should be attached to the walls, which you can hold onto while walking. Such a precaution will help prevent falls, bruises, and injuries.

So that you can sit down on the toilet with confidence, brackets should also be attached to the walls in the restroom. They will also make it easier for you to get up from the toilet afterwards.

To wash your face, you close your eyes. Not seeing surrounding objects, you can lose your balance, sway, and fall. Therefore, in this case too, a bracket next to the washbasin will not be out of place.

When washing, do not just splash water on your face, but wipe your face, neck, ears, and shoulders with some force. Such washing becomes both therapeutic exercise and a light self-massage. Some doctors recommend using an electric toothbrush, but we advise using a simple toothbrush, and it is advisable that you brush your teeth alternately with your left and right hand. In this case, the hygiene procedure turns into an easy therapeutic exercise.

In addition to washing, a man must also shave. If you manage your usual shave with lathering your cheeks and a safety razor, continue to do so. However, shaving with an electric shaver has some advantages: you do not need to lather your face, you can shave while sitting, and not necessarily in the bathroom. Of course, this should be done during those hours and days when you feel better.

Rubber mats should be placed in the bathroom next to the tub and on the bottom of the tub itself so you will not slip. To get into the tub, you should hold onto the grab bars on the walls.

It is better to take a bath while sitting, as it will be more convenient for you to lather your body. With Parkinson's disease, thermoregulation is impaired and you can easily overheat, so the water temperature should not be high.

After you have washed, it is best to dry off with a towel without leaving the tub. Then, holding onto the grab bars, you get out of the tub and put on light home clothing.

After taking a bath, you should rest for half an hour or more. Depending on your habits, you can rest in bed, on a sofa, or in an armchair. A deep, low armchair is the most unsuitable place to rest: you can fall asleep in an uncomfortable posture in it, and it can be difficult to get up from it.

Going out for shopping

If the patient manages the household independently or has the strength to help their family, they must take care of timely purchasing groceries. Proper planning for the purchase of perishable and long-storage foods is especially important when running a household independently.

There is nothing shameful about writing down in a notebook what you need to buy today, tomorrow, etc.

If you go out for groceries daily, you should determine the weight that you can easily carry home – usually 2 – 3 kg.

If circumstances are such that you have to buy more groceries at once, you should get a special shopping cart on wheels.

Meal

Each meal should be timed to the time of day when you feel more energetic. Try to eat meals at the same time every day, as the timing of many medications depends on food intake. This mainly applies to levodopa and its derivatives. The absorption of levodopa and its derivatives in the stomach depends on the rate of gastric emptying (the passage of food into the intestine) and the acidity levels of gastric juice. The presence of food in the stomach slows down and impairs the absorption of levodopa and its derivatives, and its effectiveness decreases. Therefore, it is advisable to take levodopa and its derivatives 45 - 60 minutes before a meal or one and a half to two hours after it.

The kitchen environment should be comfortable and accessible. The cooking process must be facilitated as much as possible. All foods should be prepared for consumption in advance; you only need to chop something and heat something up.

The table where you eat should be located close to where food is heated. You should not walk with a hot dish across the whole room, let alone into another room. Everything at the table should be prepared in advance: tableware, foods that you like to consume during the meal (bread, spices, water, juices, fruits, etc.).

Eat leisurely; put the contents of each subsequent spoonful into your mouth only after you have swallowed the contents of the previous spoonful or taken a sip of water. During a meal, problems related to chewing and swallowing food may arise (a piece gets stuck in the throat). This is due to the fact that, because of parkinsonism, the swallowing muscles are also weakened and cope less well with their function.

Tips to facilitate swallowing:

• sit upright while eating;

• tilt your head slightly forward when swallowing;

• eat in small portions, do not take the next portion into your mouth if the previous one is not completely swallowed;

• allocate enough time for the meal and do not talk while eating;

• drink liquids in small sips;

• consume minced food if necessary;

• concentrate on the movements of your tongue;

• drink a little liquid after each swallow of food;

• it is better to eat more often and in small amounts;

• if gastroesophageal reflux occurs, causing stomach acid to rise into the esophagus (heartburn, burping), lying down after eating is not recommended.

The consistency of food is important for swallowing. Dry or fried foods are harder to swallow and digest than boiled foods, creams, and purees. A wide variety of dishes can be prepared from the exact same foods.

If hand tremors and clumsiness of movement interfere with eating, you can use available assistive devices:

• use a straw and a lid-covered cup or a weighted cup for drinking;

• use plates fixed to the table with a raised back edge;

• the table covering should be textured;

• if the food consists of small pieces, use a spoon instead of a fork;

• wrap the handles of mugs and cutlery with something to make them wider, making them more comfortable to hold;

• for convenience, you can use a two-handled mug.

If you are tired during a meal, you should rest for half an hour. If there is no fatigue or you have already rested, leisurely wash the dishes and tidy up the prep table and the table where you eat; after that, you can also rest for half an hour.

It should not be forgotten that the composition of the food you consume can affect the absorption and effectiveness of the antiparkinsonian drugs you take. Consult your doctor or dietary consultant about what food is most suitable given the presence of a chronic disease that reduces your physical activity, while you must regularly take antiparkinsonian drugs that themselves alter appetite and affect bowel activity.

Apartment cleaning

You must correctly assess your strength – what you can do yourself during cleaning without harming your condition: dusting, vacuuming floors, carpets, and other items (e.g., a sofa), doing wet cleaning, or washing the floor.

We can give you one piece of advice: you do not need to do what healthy people sometimes do: set a goal to clean the entire apartment in half a day or a single day. When you live alone, you should never do a deep clean all at once. Do not hesitate to make a cleaning schedule for yourself and do it in parts every day of the week. This will be a useful form of exercise therapy for you.

However, you must assess your strength yourself and not undertake cleaning that is beyond your abilities.

Laundry

You need to get a washing machine that will do everything for you. But the washed and spun laundry needs to be hung out for final drying, and then it also needs to be ironed. If you do not feel confident that you can do this yourself, you should ask for help. The machine will wash the laundry, and helpers will hang it out and iron it. Tumble dryers are also available now, into which laundry is placed immediately after washing. After using some of them, you may not even need to iron the laundry.

Walking

It goes without saying that walks in the fresh air at a measured and familiar pace strengthen you, boost your mood, and energize you. Many diseases have unexplained mysteries, and Parkinson's disease has its own: for many patients, as soon as they step across the threshold of the house and go outside, their walking improves, and they gladly stride for kilometers on such walks. Therefore, we consider walks an obligatory element of daily physical activity.

In a number of cases, walks can be combined with purchasing necessary groceries or performing other household or daily chores (paying utility bills, buying household goods).

Physical activity at other times of the day

We have already listed so many options for physical activity above that little time is left for everything else. Nevertheless, sitting by the TV or radio, rustling the pages of newspapers and books is not the best pastime for a patient with movement difficulties. The more time per day spent on physical activity, the better. Do not think that the doctor does not understand that all this activity is hard-won for the patient with willpower and effort. But we always insist that the patient carry out the maximum load of household duties, provided, of course, that this does not worsen their condition.

Let's recall that fatigue after such work is not a deterioration in health, and it goes away after rest. Therefore, instead of sitting in an armchair or lying on the couch, all productive time (the time when medications are most effective) should be used practically: wipe the dust off furniture or window sills with a damp cloth or sponge, sweep (mop) the floor in the kitchen, bathroom, and toilet. Well, if you have enough energy, vacuum the rooms.

If there is time left after completing these household chores, you should perform therapeutic exercise (LFK) workouts.

Visiting and hosting guests

Communication with relatives and friends is important for everyone. Therefore, your desire for such communication and your wish to carry it out is well understood by your doctor. However, unfortunately, trips can present difficulties. In this regard, we would like to offer a few tips.

• Trips to visit others are only possible if you can tolerate transport well and have enough strength to communicate with relatives and acquaintances for several hours.

• Since the duration of the trip is difficult to predict, take your next dose of medication with you along with a small bottle of water to wash it down.

• Do not hesitate to take your medication at the prescribed time, wherever you may be.

When going out in public, you must remember that people are naturally curious about anything unusual. Therefore, they may stare at how you move. Our advice is to pay no attention to it at all.

If traveling to visit others is difficult for you, invite relatives and acquaintances to your home. Of course, their visit should coincide with the hours when you feel your best.

Preparing for sleep

Evening well-being varies among patients. Some get so tired during the day that they dream of getting to bed as soon as possible. Others may feel quite active if the timing of their evening dose was properly selected.

In accordance with your usual evening well-being, you set aside a certain time to prepare for sleep. You should prepare your medications for the next day, sorting them by the number of doses into labeled vials. Perform your evening routine and hygiene procedures and go to bed. During sleep, a person usually unconsciously changes body position in bed, while arms and legs do not go numb. With Parkinson's disease, such position changes are difficult. Experiencing discomfort, the patient wakes up and cannot immediately explain the reason for waking.

The first thing to do is to turn to the other side: brace your feet, raise your pelvis, and turn your knees and torso to the other side. Sometimes, to make turning in bed easier, special devices (rails, bars, etc.) are installed near the wall, grabbing onto which makes it easier for you to turn.

You may feel a desire to quench your thirst, so a glass of water should be prepared on the bedside table. To avoid breaking the glass and spilling water, an electric light switch should be within your reach. A plastic bottle can also be used instead of a glass.

If the urge to visit the toilet arises in the middle of the night, the path to it must be well lit.

If it is difficult for you to walk to the toilet at night or you are very afraid of falling, you should place a commode chair next to the bed in the evening on a simple chair or a low stable stool for nighttime use. After using it, go back to sleep and sleep until morning.

The next morning a new day awaits you. You must spend it no worse than today.

Tips for patients with Parkinson's disease facing a multi-hour trip by car, train, or plane

• You need to discuss the specifics of your trip with your neurologist.

• You should obtain an abstract from your doctor containing information about the course and specifics of your disease, the doses of medications you usually take, and, if necessary, recommendations on managing potential side effects.

• If you know nothing about the drug supply at your future destination, it is best to take a 1–2 month supply of medications with you.

• If you do not know whether you will be able to eat in a buffet, cafe, or restaurant during the trip, you need to take a small supply of food and drink along for the road.

• Wear comfortable clothing and shoes for the journey.

• A small inflatable pillow will allow you to travel comfortably in a car, plane, and train.

• If you have a long journey ahead, try to rest within 24 hours before the flight and within 24 hours after arrival.

• Try to drink more fluids the day before the flight and after arrival. This will allow you to drink less on the day of the flight and reduce the number of trips to the restroom.

• If no one is helping you during the trip:

– You should anticipate and evaluate taxi and porter services in advance;

– You should arrive by taxi at the medical station of the airport or railway station;

– The medical station staff, along with other personnel, will help you take your seat in the train carriage or airplane cabin;

– Once you are settled in your compartment or on board the aircraft, inform the train attendant or flight attendant about your disease, your mobility difficulties, and that you may need outside assistance with meals or using the restroom.

• Upon arrival, you must inform people in your future environment about your disease, difficulties, and the need to take medications.

• In the very first days after arrival, you should meet with the neurologist who will monitor you in the future. We hope you will meet a competent specialist and that they will continue to provide you with qualified care, but we also hope that you will approach their recommendations with caution if they demand a complete change to your usual treatment regimen.

Your behavior during episodes of deterioration during the day or over several days

Even in a healthy person, well-being varies from day to day, sometimes better, sometimes worse. This is even more common in patients with chronic diseases, including Parkinson's disease. The reasons for such changes vary: sharp meteorological fluctuations and changes in the Earth's geomagnetic field, psychological trauma and severe emotional distress associated with it, suddenly arising concomitant diseases—colds, flu, the onset or exacerbation of internal organ disorders, disruption of the usual medication schedule, or insufficient efficacy of drugs previously prescribed to you.

Having many years of experience observing and treating patients with Parkinson's disease, we know that patients themselves can generally accurately determine the causes of temporary deterioration. Nevertheless, in each individual case, it is best to consult with your doctor.

During long-term follow-up of a patient with a chronic disease, we consider it very important that you are monitored by the same physician. Usually, this is an outpatient clinic doctor. The staff of our department and Center systematically provide additional follow-up for outpatients.

If your outpatient doctor has doubts about the correctness of the prescribed treatment, they may refer you to our Center for consultation. Through the joint efforts of your doctor, our staff, and taking into account your own perceptions of the cause of deterioration or unsatisfactory condition during certain hours of the day, your treatment will be evaluated and measures will be taken to eliminate such worsening.

Diet in Parkinson's disease

The daily diet should include cereal and dairy products, fruits, vegetables, and meat/fish. Dietary fiber found in vegetables and fruits is necessary for the digestive system and helps prevent constipation, which often accompanies Parkinson's disease. Proteins can impair the absorption of dopa and its derivatives, but protein products cannot be excluded from the diet—the food must be balanced.

If you are taking levodopa, it is recommended to structure your meal plan so that low-protein foods (bread, rolls, cereals, vegetables, fruits, carbohydrates) predominate in the first half of the day. Meat, fish, eggs, and cottage cheese, which are rich in proteins, are best left for the evening. Thus, levodopa will be better absorbed during active daytime hours, while dinner will contain an adequate amount of protein.

Among grains, rice, corn, and buckwheat with a low gluten content are preferable. Carbohydrates can be consumed in any form, especially fruits and vegetables, both as a main course and as a side dish, but sweets in moderation.

Fats are divided into animal and vegetable fats; preference should be given to vegetable fats (vegetable oil, especially olive oil). The amount of animal fats and cholesterol in the diet should be relatively low (butter, lard).

It is important to consume an adequate amount of fluids. This helps combat constipation, reduces the likelihood of a drop in blood pressure, and facilitates the body's absorption of medications and food. The daily fluid intake should be sufficient—at least 6 to 8 glasses a day in addition to food. However, fluid intake in the evening should be restricted to avoid frequent nighttime trips to the bathroom. Coffee and black tea stimulate kidney function and fluid excretion from the body, depleting the body's fluid reserves. In Parkinson's disease, it is preferable to drink herbal decoctions and teas (mint, lemon, chamomile, etc.). Hard alcoholic beverages are discouraged, as alcohol has a detrimental effect on the nervous system and can interact with certain medications (including antidepressants).

Vitamins can be taken in winter and spring. Regarding dietary supplements, there are arguments both for and against, but natural foods are preferable. Evidence suggests that vitamin D deficiency negatively impacts the course of Parkinson's disease. Therefore, we advise all patients to consume more foods containing adequate amounts of it (fatty fish, fish oil, butter, cheese and other high-fat dairy products, egg yolk, caviar). Additional vitamin D supplementation must be carried out under medical supervision, and a blood test for its levels should be performed beforehand. Both a deficiency and an excess of vitamin D are harmful and even dangerous for humans.

Falls

A fall may result from impaired movement in Parkinson's disease or postural instability. However, in an elderly person, a fall can also occur due to fluctuations in blood pressure, cardiac arrhythmias, or sudden dizziness and lightheadedness.

Accidental factors can also be the cause: uneven ground (potholes, bumps), slippery floors or pavement, poor lighting, poor vision, or inattentiveness while walking, standing up, or sitting down. It is quite obvious that accidental factors can be avoided by exercising caution and paying attention to how you walk. Increased frequency of falls during the progression of Parkinson's disease may require a change in ongoing treatment.

If you fall, try to stay calm, do not rush to get up, and first "collect yourself." Try to assess your injuries—check for fractures, whether your arms and legs are responsive, and whether you are experiencing severe dizziness or cardiac irregularities. If there is someone nearby to help, do not hesitate to ask for assistance. If no one is around, try to get up on your own: first onto your hands and knees, then onto the foot of one leg, and then, using your hands to push off your knee, stand up and straighten out. All of this is easier to do if you lean against a sturdy object: at home—a sturdy chair, table, or sofa; outside—a bench, fence, or tree.

For the doctor to properly assess the situation related to the fall, you need to recall the details as best as you can and report whether there were any accidental causes for the fall (misstep, trip, slip), or if the fall was preceded by dizziness, cardiac irregularities, or chest pain. All of this will help accurately determine the cause of the fall and prevent it in the future. Recurrent falls require maximum caution when walking; use a cane and the assistance of others.

One of the causes of falls in Parkinson's disease is the loss of balance, during which the patient's body is irresistibly "carried" forward, sideways, or they begin to shuffle backward. In addition, falls frequently follow sudden freezing episodes—episodes of movement arrest where the patient is unable to take a step or engages in ineffective treading in place. Typically, such freezing episodes occur either at the initiation of walking or when changing the movement pattern—during turns, when passing through a narrow space (such as a doorway), when entering an elevator, or when stepping over a threshold. Such falls are particularly dangerous on stairs or in a dark stairwell. Being aware of your difficulties, be especially careful when turning, getting up from a sitting position, and walking up or down stairs.

Another cause of falls lies in autonomic failure, when the patient's blood pressure cannot be maintained at optimal levels and drops sharply upon transitioning to an upright position or during prolonged standing or walking. This condition is called orthostatic hypotension, which manifests as weakness, drowsiness, non-rotational dizziness, and a feeling of lightheadedness in the standing position, a desire to sit or lie down to relieve symptoms, and in some cases leads to a fall and even fainting! To confirm the presence of orthostatic hypotension, an orthostatic test is performed by measuring blood pressure in the supine and standing positions. It should be remembered that after taking certain antiparkinsonian medications, hypnotics, sedatives, diuretics, and also after meals, blood pressure drops, and the symptoms of orthostatic hypotension may intensify. Therefore, the intake of medications with a hypotensive effect should be eliminated or minimized, and you should only go outside when you are feeling well, during periods of the day when your blood pressure readings are more stable.

Recommendations for physical exercise:

1) Combine endurance and functional mobility exercises—training the strength of the knee and hip extensor muscles when getting up from a chair, the strength of the ankle plantar flexors when climbing stairs, and walking endurance with directional changes.

2) It is preferable to perform high-amplitude movements in lying, sitting, standing, or walking positions.

3) When prescribing individual resistance exercises, it is necessary to use strength exercises that target large muscle groups and involve the majority of joints.

4) Performing exercises using biofeedback is effective.

5) The exercise program should be tailored based on the set goals, while taking into account the need to perform certain activities in daily life:

- getting up from and sitting down on a chair

- lying down on and getting up from a bed

- rolling over in bed

- walking with long strides and large-amplitude arm swings (Nordic walking)

- walking with obstacles and overcoming them

- walking with sudden stops and changes in walking direction, including backward walking

- walking and maintaining balance while performing a dual task, such as talking, carrying an object, or turning the head to the left or right

- making turns in large and confined spaces:

6) Keep a fall diary. This will ensure the optimal choice of rehabilitation goals and methods, rehabilitation settings, the use of dual-tasking, addressing fear of falls, orthostatic hypotension, motor fluctuations and dyskinesias, and the need for assistive devices.

7) Gradually increase the intensity and frequency of physical exercise repetitions:

- assess exercise tolerance using the Borg scale from 13 points (moderate intensity) to 14 points or 17 points (high intensity)

- by heart rate: exercise intensity as a percentage of maximum HR (maximum heart rate is calculated using the formula 220 minus the person's age),

moderate-intensity training at 40–60% of maximum HR

high-intensity training at 40–80% of maximum HR

- by set frequency: increasing the load, speed, and number of sets from 1 to 3 with 8–15 repetitions per set (at an intensity of 60–80% of maximum HR for a single repetition, or, if not possible, a maximum of four repetitions)

8) Perform the exercise program under the supervision of a physical and rehabilitation medicine physician.

Recommendations for treadmill training:

1) Focus on the gait cycle, increasing stride length.

2) Concentrate your attention and use biofeedback.

3) Cognitive dual-tasking can be applied by asking the patient to focus on stride length.

4) Consider placing a mirror in front of the treadmill to provide visual feedback on posture.

5) Gradually increase the intensity and frequency of physical exercise repetitions:

- assess exercise tolerance using the Borg scale from 13 points (moderate intensity) to 14 points or 17 points (high intensity)

- by heart rate: exercise intensity as a percentage of maximum HR (maximum heart rate is calculated using the formula 220 minus the person's age),

moderate-intensity training at 40–60% of maximum HR

high-intensity training at 40–80% of maximum HR

- Treadmill walking speed should correspond to 60% to 80% of the 6MWD test result.

Recommendations for Tai Chi practice:

1) Combine deep breathing with slow and rhythmic movements.

2) Utilize single-leg balance, weight shifting, controlled center of mass displacement, stepping in various directions, and complex movement sequences.

3) Aim to perform movements with a large range of motion.

Recommendations for motor learning

1) Define your goal and the location for your sessions

2) Aim for repeated practice taking into account your personal physical capabilities

3) Supplement with visual and auditory stimuli (cues)

4) Gradually increase movement complexity and cognitive engagement, for example, when training dual cognitive tasks

5) Focus attention on learning, perform purposefully and consciously

6) Alternate between practice and rest

7) Consider creating mental imagery during learning

However, motor learning impairments may be evident even in the early stages of the disease due to the onset of executive cognitive dysfunction, which reduces working memory, attention, planning, task-switching, multitasking, and action initiation. In addition, anxiety, depression, or fatigue affect the ability to learn motor skills.

The efficacy of dual-task motor learning has not yet been evaluated in studies. Therefore, the recommendations lack an evidence base. Nevertheless, experimental observations have shown that during training, patients without cognitive impairment should prioritize the walking process while reducing attention to the secondary cognitive task. This is important because dual-task situations are difficult to avoid in daily life. Moreover, experimental observations have demonstrated improved dual-task walking after motor learning in the form of dual-task gait training using visual cues, specifically treadmill training with virtual visual obstacles and focusing attention on step length with or without an auditory cue. During gait training, patients should aim to improve walking speed and step length by applying visual or auditory cues while simultaneously performing various dual motor or cognitive tasks.

Examples of cognitive tasks:

- Speech speed: for example, ask the patient to name cities starting with a specific letter.

- Choice and decision making: for example, ask the patient to change their walking direction to the right when you say the word "yellow", and stop when you say "red"

- Working memory: for example, ask patients to count backward by threes starting from 90

- Mental tracking: for example, tell the patient a story and ask them to count how many times a specific word was uttered

- Reaction speed: for example, ask the patient to describe a specific route or how they spent last weekend while walking, carrying a tray with glasses filled with water, or picking up objects from a shelf

Recommendations for teaching compensatory strategies

1) Examples of cueing landmarks:

- Visual: walking along stripes on the floor

- Auditory: walking to the rhythm of a metronome or the patient's favorite music, for example, using a smartphone

- Tactile: walking in the rhythm of vibration from a vibrating wristband.

2) Cadence cueing:

- determine the average cadence using the scale

- to increase walking distance (especially outdoors) in the absence of freezing: cadence cue starting from 10% and above the average cadence

- to improve gait stability during complex actions, mainly indoors: cadence cue starting from 15% and below the average cadence

- To improve freezing of gait: cadence cue up to 10% below the average cadence

3) Examples of attentional focus strategies

- Thinking about a large step length

- Applying a cueing landmark while walking

- Making a wide turn when walking

- Lifting knees high up when walking

4) Examples of attentional focus strategies for movement initiation:

- Swaying from left to right before starting to walk

- Combining swaying with visualization of a large step length

- Taking a step back before starting to walk

- A sharp upward arm raise ("pointing the direction")

- When turning in bed: rocking the torso with bent knees from left to right before turning

- When getting up from a chair: rocking the torso forward and backward before standing up from the chair.

Recommendations for complex sequential movement strategy

1) Define your goal and the location for your sessions

2) Aim for repeated practice taking into account your personal physical capabilities

3) Supplement with visual and auditory stimuli (cues)

4) Practice in an environment where daily activity limitations exist (most often at home)

5) What to consider:

- Maintain established activity; analyze movement limitations

- Determine the most optimal (usually four to six) movement components.

- Analyze the sequence of components: using cues, accompanied by visualization.

- Have the physical ability to perform the selected components of sequential movements

- Rehearse the chosen components of sequential movements aloud

- Apply visualization of the components of sequential movements

- Perform the components of sequential movements with focused attention.

In case of cognitive impairment, pain syndrome, and fatigue

It is necessary to account for the presence of cognitive impairment, pain syndrome, and fatigue during rehabilitation and adjust baseline therapy if necessary.

In case of cognitive impairment

• Motivation is important; set achievable goals and provide positive feedback.

• In the early stages of the disease, dual cognitive tasks can be performed, while in later stages, limit them by performing tasks sequentially

• Keep information brief

• Use activities aimed at improving executive functions to maintain cognitive function

In case of pain syndrome:

• Inform the patient about the cause of the pain syndrome

• Adjust the method, load, frequency, and duration of exercises to avoid increasing the pain syndrome

In case of fatigue:

• Explain to patients what fatigue is and what it is not when performing exercises

• Adjust the method, load, frequency, and duration of exercises to avoid fatigue.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1 Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)

Original title: Unified Parkinson's Disease Rating Scale Movement Disorder Society (MDS-UPDRS)

Source: Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, LaPelle N. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan. Movement Disorders. 2007;22(1):41-47.

Type: rating scale

Purpose: identification and assessment of the severity of motor and non-motor symptoms, activities of daily living, and treatment complications

Part 1: Non-motor aspects of experiences of daily living (nM-EDL)

Introduction: This part of the scale assesses the impact of non-motor symptoms of Parkinson's disease (PD) on patients' daily activities. It contains 13 questions. Part 1A (6 questions) is administered by the investigator (physician) and focuses on the assessment of complex behaviors.

Part 1B is a questionnaire consisting of 7 questions for patient self-assessment of non-motor manifestations in daily activities.

Part 1A:

When administering Part 1A, the physician should follow these rules:

1. Indicate at the top of the form from whom the answers were obtained: the patient, the caregiver, or both the patient and the caregiver in equal proportion.
2. Answers to the questions should reflect the previous week, including the day of information collection.
3. All ratings must be whole numbers (half-point ratings or skipped items are not permitted). If a rating cannot be made for any item (e.g., the patient does not walk), NE (Not Evaluable) should be indicated for that item.
4. Answers should reflect the usual level of function and when interviewing the patient, it is necessary to use the words "usually", "most often", "most of the time".
5. Each question is accompanied by explanatory text (instructions for the patient or caregiver) that you must read out to them. After that, you may ask additional questions to assess the symptom specified in the investigator's instructions.

You MUST NOT READ THE RATING CRITERIA to the patient or caregiver, as they contain medical terminology. Based on the interview and clinical analysis, you must select the best available response for the rating.

1. The patient may have comorbid conditions or other medical states affecting their function. You and the patient should evaluate the problem as it exists, without attempting to separate the impact of PD from that of another disease.

Example of directed questioning for various response options in Part 1A.

The proposed strategies are designed to obtain the most accurate answers:

After reading the instructions to the patient, you should evaluate the function as a whole, determining through discussion whether it is normal or impaired. If your questions do not reveal an impairment of this function, then a score of 0 should be given and you should proceed to the next question.

If the questions reveal an impairment of this function, assess the severity of this impairment relative to the rating corresponding to the midpoint of the possible severity range (corresponding to a rating of 2, or mild severity of the disorder): the patient's condition may correspond to this level, be milder, or be more severe. Do not read the rating descriptions to the patient, as they use medical terminology. You must ask the patient enough questions to select an appropriate rating.

By cycling through the rating options relative to the chosen reference point, you need to find the most accurate response option while excluding the options above and below it.

Diagram

MDS-UPDRS Part 1: Non-motor aspects of experiences of daily living (nM-EDL)

Part 1A: Complex behaviors (completed by the investigator) Source of information:

Patient Caregiver Patient and caregiver equally

Read to the patient: I am going to ask you 6 questions about what is happening or perhaps not happening to you. Some questions concern common problems, others rarer ones for you. If you have a problem in one of these areas, please choose the most accurate response reflecting how you felt MOST OF THE TIME OVER THE PAST WEEK. If this problem does not bother you, you can simply answer NO. I intend to examine you as thoroughly as possible, so I will be asking about problems that you may not be experiencing.

1.1 COGNITIVE IMPAIRMENT

Investigator instructions: Assess all types of cognitive changes, including cognitive slowing, thought disorder, memory loss, attention deficits, and disorientation. Assess their impact on daily functioning from the perspective of the patient and/or caregiver.

Patient (and caregiver) instructions: Over the past week, have you experienced problems related to an inability to remember things, maintain a conversation, sustain attention, think clearly, or orient yourself at home or in the city?

(If YES, the investigator asks the patient or caregiver to provide explanatory information).

0. Normal: No cognitive impairment.

1. Slight: Recognized by the patient or caregiver, but does not interfere with the patient's ability to maintain a normal level of activity and interactions with others.

2. Mild: Clinically detectable cognitive dysfunction with minimal impact on the patient's ability to maintain a normal level of activity and interactions with others.

3. Moderate: Cognitive deficit limits, but does not preclude, the patient's ability to maintain a normal level of activity and interactions with others.

4. Severe: Cognitive dysfunction makes it impossible for the patient to maintain a normal level of activity and interactions with others.

1.2 HALLUCINATIONS AND PSYCHOSIS

Investigator instructions: Assess the presence of both illusions (distorted perception of real stimuli) and hallucinations (spontaneous false perceptions). Take into account all major sensory modalities (visual, auditory, tactile, olfactory, gustatory). Assess both unstructured (false sensations of presence or passage) and structured (clearly detailed) perceptions. Assess the patient's insight into the hallucinations, the presence of delusions, or paranoid thinking.

Patient (and caregiver) instructions: Over the past week, have you seen, heard, or felt things that did not really exist?

(If YES, the investigator asks the patient or caregiver to provide explanatory information).

0. Normal: No hallucinations or psychotic behavior.

1. Slight: Illusions or unstructured hallucinations, but the patient has insight into them.

2. Mild: Structured hallucinations not related to external stimuli, without loss of insight.

3. Moderate: Structured hallucinations with loss of insight.

4. Severe: Delusions or paranoid disorders.

1.3 DEPRESSION

Investigator instructions: Pay attention to depressed mood, sadness, hopelessness, feelings of emptiness, and loss of a sense of pleasure. Assess the presence of these manifestations and their duration over the past week, as well as their impact on the patient's ability to maintain daily activities and engage in interactions with others. Patient (and caregiver) instructions: Over the past week, have you felt depressed, sad, hopeless, or unable to enjoy things? If YES, did these manifestations persist for more than 1 day? Did these manifestations make it difficult to perform your daily tasks and communicate with people?

(If YES, the investigator asks the patient or caregiver to provide explanatory information).

0. Normal: No depression.

1. Slight: Episodes of depressed mood, each lasting no more than 1 day; without impairment of the patient's ability to maintain a normal level of activity and interactions with others.

2. Mild: Depressed mood persists for more than 1 day, but without impairment of the patient's ability to maintain a normal level of activity and interactions with others.

3. Moderate: Depressed mood limits, but does not completely eliminate, the patient's ability to maintain a normal level of activity and interactions with others.

4. Severe: Depressed mood makes it impossible for the patient to maintain a normal level of activity and interactions with others.

1.4 ANXIETY

Instructions for the examiner: Identify the presence of nervousness, inner tension, worry, or anxiety (including panic attacks) over the past week, determine their duration, and assess their impact on the patient's ability to carry out daily activities and interact with others. Instructions for the patient (and caregiver): Over the past week, have you experienced nervousness, worry, or inner tension? If YES, did these sensations last longer than 1 day? Did these symptoms interfere with your daily activities or interacting with people? (If YES, the examiner asks the patient or caregiver to provide clarifying information).

0. Normal: No anxiety.

1. Very mild: Anxiety persists for no more than 1 day at a time; does not impair the patient's ability to maintain a normal level of daily activity and interact with others.

2. Mild: Anxiety persists for more than 1 day, but does not impair the patient's ability to maintain a normal level of activity and interaction with others.

3. Moderate: Anxiety limits, but does not preclude, the patient's ability to maintain a normal level of activity and interaction with others.

4. Severe: Anxiety makes it impossible to maintain a normal level of activity and interaction with others.

1.5 APATHY

Instructions for the examiner: Assess spontaneous activity, perseverance, motivation, and initiative. Evaluate the impact of reduced levels of these characteristics on daily activities and interaction with others. The examiner should attempt to differentiate manifestations of apathy from similar symptoms most likely related to depression.

Instructions for the patient (and caregiver): Over the past week, have you noticed a lack of desire to do anything or spend time with other people?

(If YES, the physician asks the patient or caregiver to provide clarifying information).

0: Normal: No apathy.

1. Very mild: Acknowledged by the patient or caregiver, but does not affect the patient's ability to maintain a normal level of activity and interaction with others.

2. Mild: Apathy interferes with specific types of activities and interactions with others.

3. Moderate: Apathy interferes with most types of activities and interactions with others.

4. Severe: Passivity and withdrawal, complete loss of initiative.

1.6 MANIFESTATIONS OF DOPAMINE DYSREGULATION SYNDROME

Instructions for the examiner: Assess the patient's involvement in various activities, including unusual or excessive gambling (e.g., casinos or lotteries), unusual or excessive sexual desires or interests (e.g., sudden interest in pornography, masturbation, increased sexual demands on a partner), other repetitive activities (hobbies, taking things apart, sorting and organizing), or additional non-prescription medication use unrelated to medical reasons (as a manifestation of drug craving). Assess the impact of this pathological activity/behavior on the patient's daily functioning, family life, and social relationships (including the need to borrow money or other financial difficulties, such as those related to credit card debt, major family conflicts, distraction from work, skipping meals, or insufficient sleep due to these activities).

Instructions for the patient (and caregiver):

Over the past week, have you experienced unusually strong urges that were difficult to control? Have you felt the need to do something or think about something and found it difficult to stop?

(Give examples to the patient such as gambling, (preoccupation with cleanliness, computer use, excessive medication intake, increased interest in food or sex).

Use examples applicable to the specific patient)

0. Normal: No problems.

1. Very mild: Problems are present, but usually do not cause any difficulties for the patient, their family, or caregivers.

2. Mild: Problems are present and cause some difficulties in the life of the patient and their family.

3. Moderate: Problems are present and cause significant difficulties in the life of the patient and their family.

4. Severe: Problems are present and disrupt the patient's normal activities and interaction with others, or prevent maintaining the established living standards of the patient and their family.

The remaining questions in Part I (Non-Motor Aspects of Daily Living): [Sleep disturbances, Daytime sleepiness, Pain and other sensory phenomena, Urinary problems, Constipation, Lightheadedness on standing, Fatigue] are included in the Patient Questionnaire, along with all questions in Part II (Motor Aspects of Daily Living).

Patient Questionnaire

Instructions:

This questionnaire will help us learn about what you experience in daily life. It contains 20 questions. We have tried not to miss anything, and some of the questions may not apply to you at present or at all. If you do not have a particular problem, simply mark 0, which means NO. Please read each question carefully and review all proposed answer choices before marking the one that best corresponds to your condition.

We need to know your usual condition over the past week, including today. For some patients, the condition may fluctuate throughout the day. However, only one answer choice must be given for each question; please choose the one that best reflects your condition most of the time.

You may have other medical conditions besides Parkinson's disease. Do not attempt to separate their influence from that of Parkinson's disease. Simply select the best answer choice for each question.

When answering, use only scores 0, 1, 2, 3, 4 and nothing else. Do not leave blanks.

Your doctor or nurse can help clarify the meaning of a question, but the questions must be answered by the patient themselves, either independently or with the help of a caregiver.

Who filled out the questionnaire? (select the most accurate option)

Patient Caregiver Patient and caregiver equally

Part 1: Non-Motor Aspects of Daily Living (nM-EDL)

1.7 SLEEP DISTURBANCES

Did you have difficulty falling asleep at night or staying asleep through the night over the past week? How rested do you feel in the morning after sleep?

0. Normal: No disturbances.

1. Very mild: Sleep disturbances are present, but usually do not prevent sleeping through the entire night.

2. Mild: Sleep disturbances cause some difficulties that prevent sleeping through the entire night.

3. Moderate: Sleep disturbances cause significant difficulties that prevent sleeping through the entire night, but I usually sleep more than half the night.

4. Severe: I usually do not sleep for most of the night.

1.8 DAYTIME SLEEPINESS

Did you find it difficult to stay awake during the day over the past week?

0. Normal: No daytime sleepiness.

1. Very mild: Daytime sleepiness occurs, but I can resist it and remain awake.

2. Mild: I occasionally fall asleep when I am alone and in a relaxed state, such as when reading or watching television.

3. Moderate: I occasionally fall asleep at inappropriate times, such as when eating or talking with other people.

4. Severe: I frequently fall asleep at inappropriate times, such as when eating or talking with other people.

1.9 PAIN AND OTHER SENSORY PHENOMENA

Did you experience unpleasant bodily sensations over the past week, such as pain, heaviness, tingling, or painful muscle spasms?

0. Normal: No unpleasant sensations.

1. Very mild: I have unpleasant sensations, but this does not prevent me from doing things or interacting with other people.

2. Mild: These sensations cause me some inconvenience when I am doing things or interacting with other people.

3. Moderate: These sensations create significant problems, but they do not force me to stop doing things or avoid contact with other people.

4. Severe: These sensations force me to stop doing things or avoid contact with other people.

1.10 URINARY PROBLEMS

Did you experience problems with bladder control over the past week? For example, sudden urges to urinate, too frequent urination, or urine leakage?

0. Normal: No disturbances.

1. Very mild: I have frequent or sudden urination that can be difficult to control, but these problems do not interfere with my daily activities.

2. Moderate: Urination problems cause some difficulty in my daily activities, but I do not experience urine leakage.

3. Severe: Urination problems cause significant difficulty in my daily activities, including those related to urine leakage.

4. Very severe: I cannot control my urination and use diapers or a urinal, or I have a urinary catheter.

1.11 CONSTIPATION

Have you typically experienced difficulty with bowel movements over the past week?

0. Normal: No constipation.

1. Very mild: I have constipation and need to strain during bowel movements, but this does not disrupt my activity or comfort.

2. Mild: Constipation somewhat impairs my daily functioning or serves as a source of discomfort.

3. Moderate: Constipation significantly impairs my daily functioning and serves as a source of discomfort, but does not force me to refrain from any activities.

4. Severe: I am forced to rely on physical assistance from another person to have a bowel movement.

1.12 DIZZINESS UPON STANDING

Have you experienced fainting, dizziness, or unsteadiness over the past week when standing up from a sitting or lying position?

0. Normal: No feeling of dizziness or unsteadiness upon standing.

1. Very mild: Upon standing up, I experience feelings of

dizziness or unsteadiness, but they do not impair my daily life.

2. Mild: Feelings of dizziness or instability make me hold onto something, but I do not need to sit or lie down.

3. Moderate: Feelings of dizziness or instability make me sit or lie down to avoid falling or losing consciousness.

4. Severe: I fall or lose consciousness due to dizziness or feelings of instability.

1.13 FATIGUE

Have you felt constant fatigue over the past week? Moreover, this sensation is not related to drowsiness or a sad mood.

0. Normal: No fatigue.

1. Very mild: Fatigue is present, but does not interfere with daily activities or socializing with other people.

2. Mild: Fatigue causes some difficulty with activities or contact with other people.

3. Moderate: Fatigue causes significant difficulty with activities or contact with other people.

4. Severe: Fatigue forces me to stop all activity or contact with other people.

Part II MOTOR ASPECTS OF EXPERIENCES OF DAILY LIVING

2.1 Speech

Over the past week, have you usually had problems with your speech?

0. Normal: No problems.

1. Very mild problems: My speech is not loud, clear, or distinct enough, but other people do not have to ask me to repeat myself.

2. Mild problems: My speech causes other people to sometimes ask me to repeat myself, but not every day.

3. Moderate impairment: Because of my speech indistinctness, other people have to ask me to repeat myself every day, although most of my speech is understandable.

4. Severe impairment: Most or all of my speech remains entirely incomprehensible.

2.2. SALIVA AND DROOLING

Over the past week, have you typically experienced excessive saliva production while awake or asleep?

0. Normal: No problems.

1. Very mild: I have too much saliva, but it does not drool out of my mouth.

2. Mild: I have some drooling during sleep, but none while awake.

3. Moderate: I have some drooling while awake, but I do not usually need napkins or a handkerchief.

4. Severe: I drool so much that I regularly need to use napkins or a handkerchief to protect my clothing.

2.3 CHEWING AND SWALLOWING

Over the past week, have you typically had trouble swallowing pills or eating food? Do you need to crush pills or eat softer, mashed, or pureed foods to avoid choking?

0. Normal: No problems.

1. Very mild impairment: I notice slowed chewing or need extra effort when swallowing, but I do not choke and do not need specially prepared food.

2. Mild impairment: I have to split my pills or specially prepare food because of chewing or swallowing problems, but I have not choked even once over the past week.

3. Moderate impairment: I have choked at least once over the past week.

4. Severe: I require tube feeding due to chewing and swallowing problems.

2.4 EATING

Over the past week, have you typically experienced difficulties eating or using utensils? For example, difficulty holding food with your fingers, or using a knife, fork, spoon, or chopsticks.

0. Normal: No problems.

1. Very mild impairment: Eating is slowed, but I do not need help and I eat neatly.

2. Mild impairment: Eating is slowed and I sometimes drop food; I may need help with certain actions, such as cutting meat.

3. Moderate impairment: I need help with many actions related to eating, but I can perform some on my own.

4: Severe impairment: I need help with all or almost all actions related to eating.

2.5 DRESSING

Over the past week, have you experienced difficulty dressing? For example, did you dress slowly, or did you need help buttoning or zipping, putting on or taking off clothes or jewelry?

0. Normal: No problems.

1. Very mild impairment: I dress slowly, but I do not need help.

2. Mild impairment: I dress slowly, and I need help with certain actions (e.g., buttoning or putting on a bracelet).

3. Moderate impairment: I need help with many dressing actions.

4. Severe impairment: I need help with most or all actions related to dressing.

2.6 HYGIENE

Over the past week, have you noticed slowness or the need for assistance with washing, bathing, shaving, brushing teeth, combing hair, or performing other personal hygiene tasks?

0. Normal: No problems.

1. Very mild impairment: I do everything slowly, but I do not need outside help.

2. Mild impairment: I need outside help with certain hygiene procedures.

3. Moderate impairment: I need help with many hygiene procedures.

4. Severe impairment: I need help with most or all hygiene procedures.

2.7 HANDWRITING

Over the past week, have you typically noticed that people have difficulty reading what you have written?

0. Normal: No problems.

1. Very mild impairment: I write slowly, awkwardly, or clumsily, but all words are legible.

2. Mild impairment: Some words are illegible and difficult to read.

3. Moderate impairment: Many words are illegible and difficult to read.

4. Severe impairment: Most or all words are illegible.

2.8 HOBBIES AND OTHER ACTIVITIES

Over the past week, have you typically experienced difficulty in pursuing your hobbies or other activities that you would like to do?

0. Normal: No problems.

1. Very mild impairment: I am a little slow, but I easily manage these activities.

2. Mild impairment: I experience some difficulty with these activities.

3. Moderate impairment: I experience significant difficulty with these activities, but I manage most of them.

4. Severe impairment: I cannot manage all or most of these activities.

2.9 TURNING IN BED

Over the past week, have you typically had difficulty turning over in bed?

0. Normal: No problems.

1. Very mild impairment: I have some difficulty turning over in bed, but I do not need help.

2. Mild impairment: I have significant difficulty turning over in bed, and I occasionally need assistance.

3. Moderate impairment: I frequently need assistance from another person to turn over in bed.

4. Severe impairment: I cannot turn over in bed without assistance.

2.10 TREMOR

Over the past week, have you typically experienced shaking?

0. Normal: No, I do not experience shaking.

1. Very mild: Shaking occurs, but it does not interfere with any activities.

2. Mild: Shaking interferes only with certain activities.

3. Moderate: Shaking interferes with many of my daily activities.

4. Severe: Shaking interferes with all or almost all activities.

2.11 GETTING OUT OF BED, A CAR SEAT, OR A DEEP ARMCHAIR

Over the past week, have you typically had difficulty getting out of bed, a car seat, or a deep armchair?

0. Normal: No problems.

1. Very mild impairment: I get up slowly or awkwardly, but I can usually do it on the first attempt.

2. Mild impairment: It takes me more than one attempt to stand up, or I occasionally need help.

3. Moderate impairment: I occasionally need help to stand up, but in most cases, I can do it independently.

4. Severe impairment: I need help in most cases or always.

2.12 WALKING AND BALANCE

Over the past week, have you typically had difficulty with balance and walking?

0. Normal: No problems.

1. Very mild impairment: I am a little slowed down or may drag a leg, but I never use assistive devices when walking.

2. Mild impairment: I sometimes use assistive devices when walking, but I do not need assistance from another person.

3. Moderate impairment: I usually use assistive devices [cane or walker] when walking to avoid falling, but I do not usually need assistance from another person.

4. Severe impairment: I usually need the support of another person to avoid falling while walking.

2.13 FREEZING

Over the past week, have you typically noticed that you suddenly stop or freeze while walking, as if your feet are glued to the floor?

0. Normal: No problems.

1. Very mild: I experience brief freezing episodes, but I can easily resume movement; I do not need assistance from another person or assistive devices (cane or walker) due to freezing.

2. Mild: I experience freezing episodes and find it difficult to resume movement, but I do not need assistance from another person or assistive devices (cane or walker) due to freezing.

3. Moderate: When freezing, I find it very difficult to resume movement, and because of this, I occasionally have to resort to assistance from another person or assistive devices.

4. Severe: Due to freezing, I need assistive devices or assistance from another person most of the time or constantly.

This is the end of the questionnaire. During the survey, we may have asked you about problems you have never had and never will have. Not all patients develop all these problems, but they are possible, so it is important for every patient to answer all the questions asked.

Thank you for your time and for carefully completing the questionnaire.

Part III

MOTOR EXAMINATION

Introduction: This part of the scale is designed to assess the motor symptoms of PD. When performing Part III of the MDS-UPDRS, the examiner must follow these instructions:

At the top of the form, indicate whether the patient is taking medications for Parkinson's disease symptoms, and if they are taking levodopa and its derivatives, the time elapsed since the last dose.

In addition, if the patient is taking medications for Parkinson's disease symptoms, note the clinical state of the patient using the following definitions:

"ON" - the typical functional state during medication action with a good response to it.

"OFF" - the typical functional state in the absence of an adequate response to medication.

The examiner must "rate what they see with their own eyes." Obviously, comorbid medical problems such as stroke, paralysis, arthritis, contractures, and orthopedic pathology, e.g., hip or knee replacement and scoliosis, may impair the performance of individual motor examination items. In situations where a test is absolutely impossible to perform (e.g., due to amputation, plegia, or a limb cast), use the "NE" (Not Evaluable) rating. In other cases, evaluate the performance of each test as executed by the patient in the context of comorbid conditions. All items must be scored with a whole number (half-point scores or skipped items are not permitted).

Separate instructions are provided for testing each item. They must be strictly followed. The examiner describes the task to the patient, demonstrates how to perform it, and assesses the function immediately afterwards. The items assessing Global Spontaneity of Movement and Rest Tremor (3.14 and 3.17) are intentionally placed at the end of the scale, as the clinical information required for their assessment will be obtained throughout the entire examination.

At the end, indicate whether dyskinesias (dystonia or chorea) were present at the time of examination, and if so, whether they interfered with the assessment of motor functions.

3a. Is the patient taking medications for Parkinson's

disease symptoms?

No Yes

3b. If the patient is taking medications for Parkinson's disease symptoms, indicate the patient's clinical status using the following definitions:

On: On is the typical functional state of a patient when medication is in effect and responding well.

Off: Off is the typical functional state of a patient when there is no adequate response to medication.

3c. Is the patient taking levodopa No Yes

3c1. If YES, how many minutes have passed since the last dose of dopaminergic drugs and their derivatives:

3.1 SPEECH

Instructions for the examiner: Listen to the patient's spontaneous speech and engage them in conversation if necessary. Suggested topics: ask the patient about their work, hobbies, physical activity, and how they traveled to the medical facility. Assess volume, modulation (prosody), clarity of speech, and note the presence of slurring, palilalia (repetition of syllables), and tachyphemia (rapid speech with merging of adjacent syllables).

0. Normal: No disturbances.

1. Very mild impairment: Impaired modulation, diction, or volume, but all spoken words remain easy to understand.

2. Mild impairment: Impaired modulation, diction, or volume, but only isolated words are unclear, and the overall meaning of the phrases is easy to grasp.

3. Moderate impairment: Speech comprehension is impaired to the extent that some, but not most, phrases are unintelligible.

4. Severe impairment: Most phrases are completely or partially unintelligible.

3.2 FACIAL EXPRESSION

Instructions for the examiner: Observe the patient sitting at rest for 10 seconds without conversation, as well as during conversation. Note blink frequency, facial masking or loss of facial expression, spontaneous smiling, and lip closure.

0. Normal: Normal facial expression.

1. Very mild impairment: Barely noticeable facial masking, manifested only by a decreased blink frequency.

2. Mild impairment: In addition to decreased blink frequency, facial masking also affects the lower half of the face, specifically reduced mouth movements such as less spontaneous smiling, but the mouth is not half-open.

3. Moderate impairment: Masked facies, mouth half-open at rest for some of the time.

4. Severe impairment: Masked facies, mouth half-open at rest for most of the time.

3.3 RIGIDITY

Instructions for the examiner: Rigidity is assessed by the slowing of passive movements in large joints while the patient is relaxed and the examiner moves their limbs and neck. Initially, assessment is performed without activating maneuvers. Muscle tone in the neck and each limb is examined and graded separately. When examining the arm, movements in the wrist and elbow joints are tested simultaneously. When examining the leg, movements in the hip and knee joints are tested simultaneously. If rigidity is not detected, use activating maneuvers, such as tapping fingers, opening and closing the fist, or tapping the heel of the limb not being tested. Ask the patient to relax as much as possible when testing for rigidity.

0. Normal: No rigidity.

1. Very mild: Rigidity detected only with activating maneuver.

2. Mild: Rigidity detected without activating maneuvers, but full range of motion is easily achieved.

3. Moderate: Rigidity detected without activating maneuvers, full range of motion is achieved with effort.

4. Severe: Rigidity detected without activating maneuvers, full range of motion is not achieved.

neck

right arm

left arm

right leg

left leg

3.4 FINGER TAPPING

Instructions for the examiner: Each hand is tested separately. Demonstrate the task, but do not continue demonstrating while the patient performs it. Ask the patient to tap their index finger on their thumb 10 times as quickly and with as large an amplitude as possible. Each side is scored separately, taking into account speed, amplitude, hesitations and halts in movement, and amplitude decrement over time.

0. Normal: No impairment

1. Very mild impairment: Any of the following: a) rhythm interrupted with one or two interruptions or hesitations in tapping movements, b) very slight slowness, c) amplitude decrement towards the end of the 10-movement series.

2. Mild impairment: Any of the following: a) 3–5 halts in tapping; b) mild slowness, c) amplitude decrement by the middle of the 10-movement series.

3. Moderate impairment: Any of the following: a) more than 5 short halts or at least one prolonged halt in ongoing movement (freezing), b) moderate slowness, c) amplitude decrement starting after the first tap.

4. Severe impairment: Unable to perform or performs with great difficulty due to slowness, halts, or amplitude decrement.

right arm

left arm

3.5 HAND MOVEMENTS

Instructions for the examiner: Each hand is tested separately. Demonstrate the task, but do not continue demonstrating while the patient performs it. Ask the patient to make a tight fist, with the forearm flexed at the elbow so that the patient's palm faces the examiner. The patient should open the hand 10 times as fully and as quickly as possible. If the patient does not make a tight fist and open it fully, remind them to do so. Each side is scored separately, taking into account speed, amplitude, hesitations and halts in movement, and amplitude decrement over time.

0. Normal: No disturbances.

1. Very mild impairment: Any of the following: a) rhythm interrupted with one or two interruptions or hesitations in movements, b) very slight slowness, c) amplitude decrement towards the end of the movement series.

2. Mild impairment: Any of the following: a) 3–5 halts during movement performance, b) mild slowness, c) amplitude decrement by the middle of the movement series.

3. Moderate impairment: Any of the following: a) more than 5 short halts or at least one prolonged halt in ongoing movement (freezing), b) moderate slowness, c) amplitude decrement after the first fist opening-closing cycle.

4. Severe impairment: Unable to perform or performs with great difficulty due to slowness, halts, or amplitude decrement.

right arm

left arm

3.6 PRONATION-SUPINATION MOVEMENTS OF HANDS

Instructions for the examiner: Each hand is tested separately. Demonstrate the task, but do not continue demonstrating while the patient performs it. Ask the patient to extend their arm in front of them palm down, then turn the palm alternately up and down 10 times with maximum possible speed and amplitude. Examine each side separately, paying attention to speed, amplitude, hesitations and halts in movement, and progressive amplitude decrement.

0. Normal: No disturbances.

1. Very mild impairment: Any of the following: a) rhythm interrupted with one or two interruptions or hesitations in movements, b) very slight slowness, c) amplitude decrement towards the end of the movement series.

2. Mild impairment: Any of the following: a) 3–5 halts during movement performance, b) mild slowness, c) amplitude decrement by the middle of the movement series.

3. Moderate impairment: Any of the following: a) more than 5 short halts or at least one prolonged halt in ongoing movement [freezing], b) moderate slowness, c) amplitude decrement after the first pronation-supination cycle.

4. Severe impairment: Unable or barely able to perform the task due to slowness, halts, or amplitude decrement.

right arm

left arm

3.7 TOE TAPPING

Instructions for the examiner: The patient should sit in a straight-backed chair with armrests, with both feet flat on the floor. Each foot is examined separately. Demonstrate the task, but do not continue demonstrating while the patient performs it. Ask the patient, in a comfortable position with their heel on the floor, to tap their toes 10 times with maximum possible amplitude and speed. Examine each side separately, paying attention to speed, amplitude, hesitations and halts in movement, and progressive amplitude decrement.

0. Normal: No disturbances.

1. Very mild impairment: Any of the following: a) rhythm interrupted with one or two interruptions or hesitations in movements, b) very slight slowness, c) amplitude decrement towards the end of the 10-movement series.

2. Mild impairment: Any of the following: a) 3–5 halts during movement performance, b) mild slowness, c) amplitude decrement by the middle of the movement series.

3. Moderate impairment: Any of the following: a) more than 5 short halts or at least one prolonged halt in ongoing movement (freezing), b) moderate slowness, c) amplitude decrement after the first tap.

4. Severe impairment: Unable or barely able to perform the task due to slowness, halts, or amplitude decrement.

right leg

left leg

3.8 LEG AGILITY

Instructions for the examiner: The patient should sit in a straight-backed chair with armrests in a comfortable position, with feet flat on the floor. Each leg is examined separately. Demonstrate the task, but do not continue demonstrating while the patient performs it. Ask the patient to place the foot on the floor in a comfortable posture and then tap it by raising and lowering the foot 10 times with the maximum possible amplitude and speed. Assess each side separately, paying attention to speed, amplitude, hesitations and arrests of movement, and gradual decrease in amplitude.

0. Normal: No disturbances.

1. Very mild impairment: Any of the following: a) rhythm impaired with one or two movement arrests or hesitations, b) very slight slowness, c) decrease in amplitude towards the end of the task.

2. Mild impairment: Any of the following: a) 3 to 5 movement arrests, b) slight slowness, c) decrease in amplitude by the middle of the task.

3. Moderate impairment: Any of the following: a) more than 5 brief arrests or at least one prolonged arrest of ongoing movement [freezing], b) moderate slowness, c) decrease in amplitude after the first movement.

4. Severe impairment: Unable or barely able to perform the task due to slowness, halts, or amplitude decrement.

right leg

left leg

3.9 CHAIR RISE

Instructions for the examiner: The patient should sit in a straight-backed chair with armrests, with feet flat on the floor and back against the backrest (unless the patient is too short). Ask the patient to cross their arms across the chest and then stand up. If unsuccessful, ask them to repeat the attempt, but no more than 2 times. If attempts are still unsuccessful, allow the patient to slide forward to the edge of the seat and rise with crossed arms. Only one attempt is permitted in this situation. If unsuccessful, allow the patient to rise from the chair by pushing up with their hands on the armrests. A maximum of 3 such attempts is allowed. If they are unsuccessful, help the patient up. After the patient has stood up, assess their posture according to item 3.13.

0. Normal: No impairment. Able to rise quickly without hesitation.

1. Very mild impairment: Rises slower than normal, or requires more than one attempt to rise, or must slide forward to the edge of the seat; but rises without pushing off from the armrests.

2. Mild impairment: Rises without difficulty, but only when pushing off from the chair armrests.

3. Moderate impairment: Rises only by pushing off from the chair armrests, but falls back, or is forced to make several attempts while pushing off from the armrests, but is able to stand without assistance.

4. Severe impairment: Unable to rise without assistance.

3.10 GAIT

Instructions for the examiner: Gait is best assessed by asking the patient to walk away from the examiner and return, observing them in such a way that both the right and left sides of the body are clearly visible simultaneously. The patient should walk at least 10 meters, then turn around and return to the examiner. This item evaluates multiple parameters: step length, foot clearance, heel strike during walking, turns, and arm swing, but not freezing. Evaluation of gait freezing is performed in the next item (3.11). Pay attention to posture for item 3.13.

0. Normal: No disturbances.

1. Very mild impairment: Walks independently, gait is minimally altered.

2. Mild impairment: Walks independently, but gait is significantly altered.

3. Moderate impairment: Assistive devices required for safe walking [cane, walker], but no assistance from another person.

4. Severe impairment: Unable to walk at all or walks only with personal assistance.

3.11 FREEZING OF GAIT

Instructions for the examiner: When assessing gait, also evaluate the presence of any freezing episodes. Pay attention to hesitations and shuffling, especially when turning and reaching the end of the task. If safe, the patient SHOULD NOT use sensory tricks to overcome freezing during the examination.

0. Normal: No freezing.

1. Very mild: Freezing occurs at movement initiation, turning, or passing through a doorway with a single stop in any of these situations, but then the patient can resume movement smoothly without freezing during straight-line walking.

2. Mild: Freezing at movement initiation, turning, or passing through a doorway with more than one stop in any of these situations, but then the patient can resume movement smoothly without freezing during straight-line walking.

3. Moderate: Single freezes during straight-line walking.

4. Severe: Multiple freezes during straight-line walking.

3.12 POSTURAL STABILITY

Instructions for the examiner: To test the response to sudden displacement, the patient—who should stand upright with eyes open and feet comfortably apart and parallel—is pushed firmly and quickly on the shoulders. This tests retropulsion. Stand behind the patient and explain what will happen. Warn them that they may take a step back to avoid falling. There should be a sturdy wall behind the examiner at a distance of at least 1 to 2 m to allow assessment of the number of retropulsive steps. The first push, which is weaker, is given as a practice trial and is not scored. The second time, the examiner pushes the patient sharply and firmly on the shoulders with sufficient force to displace the patient's center of gravity so that the patient MUST take a step back. The examiner must be ready to support the patient, while standing behind at a distance that allows the patient to take several steps to regain balance independently. Do not allow the patient to lean the torso too far forward in anticipation of the push. When scoring, take into account the number of steps backward or a fall. Recovering balance with one or two steps is considered normal; the test is rated as abnormal starting from three steps. If the patient did not understand the test, the examiner may repeat it. When scoring the test, the examiner should take into account the patient's physical frailty rather than poor understanding or lack of readiness for the test. Assess the patient's standing posture for item 3.13.

0. Normal: No impairment. Recovers balance with 1 or 2 steps.

1. Very mild impairment: Takes 3 to 5 steps, but recovers balance independently.

2. Mild impairment: Takes more than 5 steps, but recovers balance independently.

3. Moderate impairment: Balance is maintained while standing, but when pushed, postural responses are absent and the patient falls unless caught by the examiner.

4. Severe impairment: Very unstable, loses balance spontaneously or with a light push on the shoulders.

3.13 POSTURE

Instructions for the examiner: Posture is assessed with the patient standing upright after rising from a chair, while walking, and during postural reflex testing. If you note abnormal posture, ask the patient to straighten up and assess whether the posture improves (see item 2 below). Assess the worst posture observed in these three situations. Both forward flexion and lateral flexion are taken into account.

0. Normal: No disturbances.

1. Very mild impairment: Posture is not completely erect, but can be considered normal for an elderly person.

2. Mild impairment: Distinct posture change in the form of forward flexion, scoliosis, or lateral tilt, but can straighten up and assume a normal posture upon request.

3. Moderate impairment: Stooped posture, scoliosis, or lateral tilt that cannot be corrected voluntarily by the patient.

4. Severe impairment: Marked postural deformity in the form of flexion, scoliosis, or lateral tilt.

3.14 GLOBAL SPONTANEITY OF MOVEMENT (TRUNCAL BRADYKINESIA)

Instructions for the examiner: This assessment is global and is determined by slowness, hesitancy, small amplitude, and overall poverty of movement, including reduced gesturing and leg crossing, which may be observed throughout the examination. The assessment is based on the examiner's overall impression after observing the patient's spontaneous gestures while sitting, rising, and walking.

0. Normal: No disturbances.

1. Very mild impairment: Very slight general slowness and poverty of spontaneous movements.

2. Mild impairment: Slight general slowness and poverty of spontaneous movements.

3. Moderate impairment: Moderate general slowness and poverty of spontaneous movements.

4. Severe impairment: Severe general slowness and poverty of spontaneous movements.

3.15 POSTURAL TREMOR OF THE HANDS

Instructions for the examiner: This item must take into account any tremor observed in the specified posture, including rest tremor, re-emergent posture tremor Each hand is evaluated separately. The maximum observed amplitude of the tremor is taken into account. Ask the patient to hold their arms straight out in front of them, palms down. The wrists should be straight and the fingers comfortably spread so that they do not touch each other. Observe this posture for 10 seconds.

0. Normal: No tremor.

1. Slight: Tremor is present, but its amplitude is less than 1 cm.

2. Mild: Tremor is present, its amplitude is at least 1 cm, but less than 3 cm.

3. Moderate: Tremor is present, its amplitude is at least 3 cm, but less than 10 cm.

4. Severe: Tremor with an amplitude of 10 cm or more.

right arm

left arm

3.16 KINETIC TREMOR OF THE HANDS

Instructions for the examiner: This item evaluates tremor detected using the finger-to-nose test. First, the patient is asked to stretch their arm forward and then alternately touch their nose and the examiner's finger. The test is performed with each hand at least three times. The finger-to-nose test should be performed slowly enough not to miss tremor, which may become unnoticeable with very rapid arm movement. Then the test is repeated with the other hand. Each hand is evaluated separately. Tremor may be noted throughout the movement or appear only when reaching one of the targets (nose or finger). The maximum observed amplitude of the tremor is taken into account.

0. Normal: No tremor.

1. Slight: Tremor is present, but its amplitude is less than 1 cm.

2. Mild: Tremor is present, its amplitude is at least 1 cm, but less than 3 cm.

3. Moderate: Tremor is present, its amplitude is at least 3 cm, but less than 10 cm.

4. Severe: Tremor with an amplitude of 10 cm or more.

Right hand

Left hand

3.17 REST TREMOR AMPLITUDE

Instructions for the examiner: This and the following item are intentionally placed at the end of the examination so that there is an opportunity to observe rest tremor, which may appear at any time while sitting still, and may also be noted in parts of the body that remain motionless when walking or performing other tasks. The maximum observed amplitude is taken as the final score. Consider only the amplitude of the tremor, not its persistence or intermittent nature. During the test, the patient should sit quietly in a chair for 10 seconds, with feet comfortably supported, and hands resting on the armrests of the chair (not on the knees). No other tasks are performed at this time. Rest tremor is evaluated separately for each of the four limbs and for the lips/chin. The maximum amplitude of tremor noted at any time during the examination is taken as the final score.

Limb tremor score

0. Normal: No tremor.

1. Slight: Maximum tremor amplitude ≤ 1 cm.

2. Mild: Maximum amplitude greater than 1 cm, but less than 3 cm.

3. Moderate: Maximum amplitude 3 - 10 cm.

4. Severe: Maximum amplitude greater than 10 cm.

Lip or chin tremor score

0. Normal: No tremor.

1. Slight: Maximum tremor amplitude ≤ 1 cm.

2. Mild: Maximum amplitude > 1 cm, but ≤ 2 cm.

3. Moderate: Maximum amplitude > 2, but ≤ 3 cm.

4. Severe: Maximum amplitude > 3 cm.

Right hand Left hand

Right leg Left leg

Lips or chin

3.18 REST TREMOR CONSTANCY

Instructions for the examiner: This item involves assessing the constancy of rest tremor throughout the examination when a particular body part is at rest. A single score is given for rest tremor of all locations. It is advisable to assign this score at the end of the examination, as it requires synthesizing information obtained throughout the entire assessment.

0. Normal: No tremor.

1. Slight: Rest tremor is present ≤ 25% of the total examination period.

2. Mild: Rest tremor is present for 26%-50% of the total examination period.

3. Moderate: Rest tremor is present for 51%-75% of the total examination period.

4. Severe: Rest tremor is present for more than 75% of the total examination period.

EFFECT OF DYSKINESIA ON UPDRS PART III RATINGS

A. Were dyskinesias (chorea or dystonia) present during the examination?

NO

YES

B. If yes, did these movements affect your rating?

NO

YES

HOEHN AND YAHR STAGING SCALE

Stage 0 Asymptomatic

Stage 1 Unilateral involvement only

Stage 2 Bilateral involvement without impairment of balance

Stage 3 Mild to moderate bilateral disease; some postural instability; physically independent, needs assistance to recover balance on pull test.

Stage 4 Severe disability; still able to walk or stand unassisted

Stage 5 Wheelchair bound or bedridden unless aided

Part IV MOTOR COMPLICATIONS

Introduction and instructions: In this section, the examiner assesses two types of motor complications based on history and objective information: dyskinesias and motor fluctuations (including off-period dystonia). Use all information obtained from the patient, caregiver, and during the examination to answer 6 questions reflecting the patient's functional status over the past week, including today. As in other sections, use only whole numbers for scoring (fractional scores are not allowed) and leave no blanks. If scoring for this item is not possible, indicate NE (not evaluable). You will have to choose some response options expressed as percentages, for which you will need to estimate the duration of the waking day in hours and use this number as a denominator when determining the relative duration of off-time and dyskinesias. When assessing off-period dystonia, the total duration of off-time will serve as the denominator.

Operational definitions for the examiner.

Dyskinesias: involuntary random movements.

Patients often describe dyskinesias as "non-rhythmic jerks", "rocking", "muscle contractions". It is necessary to emphasize to the patient the distinction between dyskinesias and tremor (a common patient error when assessing dyskinesias).

Dystonia: a twisting posture, often with a rotational component.

Patients often describe dystonia as "spasms", "cramping", "posture changes".

Motor fluctuations: Variable response to medications:

Patients often describe motor fluctuations as: "wearing off", "shortening of effect", "rollercoaster effect", "on-off effect", "unpredictable drug effect".

"Off": the typical functional state of a patient who does not respond to the taken medication or the typical functional reaction of a patient to the discontinuation of antiparkinsonian drugs.

Patients often describe "off" periods as "bad period", "worsening period", "tremor period", "slowness period", "period when my medications don't work".

"On": the typical functional state that occurs after taking medication in a well-responding patient.

Patients often describe "on" periods as "good time", "walking time", "time when my medications work".

A. DYSKINESIAS (excluding off-period dystonia)

4.1 DYSKINESIA DURATION

Instructions for the examiner: Determine how many hours a day the patient is typically awake and how long dyskinesias last. Calculate the percentage. If dyskinesias are present during the doctor's appointment, you can point them out to the patient or caregiver as an example to help them understand what they should be assessing. You can also use your acting skills to demonstrate what the patient's previously observed dyskinesias looked like or mimic involuntary movements typical of other patients. Exclude early morning painful dystonia or nighttime dystonia from this question.

Instructions for the patient (and caregiver).

Over the past week, on average, how many hours per day did you sleep, including both nighttime sleep and daytime naps? So, if you slept ___ hours, you spent ____ hours awake. Out of the total hours spent awake, how many total hours did you experience twitching, muscle contractions, rocking, and other involuntary movements? Do not include times when you experienced tremor (rhythmic alternating shaking movements), painful foot spasms, or spasms during the early morning and nighttime hours. I will ask you about these symptoms later. Focus only on the specified types of twitching, rocking, and non-rhythmic movements. Sum up all the hours during wakefulness when you typically experienced these movements. The total comes to ____ hours (use this number for your calculations).

0. Normal: No dyskinesias.

1. Very mild: No more than 25% of waking time.

2. Mild: 26–50% of waking time.

3. Moderate: 51–75% of waking time.

4. Severe: More than 75% of waking time.

CALCULATION

1. Total duration of wakefulness, _____ hours
2. Total duration of dyskinesias, ____ hours
3. % dyskinesias = (2 / 1) × 100 ___

4.1 FUNCTIONAL IMPACT OF DYSKINESIAS

Investigator instructions: Determine the extent to which dyskinesias affect the patient's daily functions, including activities of daily living and interactions with others. Use the responses of the patient and caregiver to your questions and your own observations during the patient examination for the most accurate assessment.

Patient (and caregiver) instructions: Over the past week, have you typically experienced difficulty with certain activities or interactions with others that were related to twitching and other involuntary movements? Did these cause you to refrain from certain activities or from interacting with other people?

0. Normal: No dyskinesias, or they have no impact on the patient's daily functioning or interactions with others.

1. Very mild: Dyskinesias affect specific activities; however, the patient generally performs all activities and interacts with others during dyskinesia episodes.

2. Mild: Dyskinesias affect many activities; however, the patient generally performs all activities and interacts with others during dyskinesia episodes.

3. Moderate: Dyskinesias affect the patient to such a degree that the patient is generally unable to perform some activities or usually refrains from certain interactions with others during dyskinesia episodes.

4. Severe: The functional impact of dyskinesias is so great that the patient generally does not perform most activities or refrains from most interactions with others during dyskinesia episodes.

B. MOTOR FLUCTUATIONS

4.3 DURATION OF "OFF" STATES

Investigator instructions: Based on total waking time (item 4.1), determine the number of hours spent in the "off" state and their percentage share. If the patient is in an "off" state during the clinic visit, you may refer to this state as an example. You can also rely on your previous observations of typical "off" periods in this patient. Additionally, you may use your acting skills to portray the patient's state during an "off" period that you previously observed in them or demonstrate typical "off" symptoms seen in other patients. Indicate the typical duration of "off" time in hours, as you will need this figure for item 4.6.

Patient (and caregiver) instructions: Some patients with Parkinson's disease experience a good response to medications throughout their waking period, which we call the "on" period. Other patients taking their medications nonetheless experience periods of worsening, slowed movement, or increased tremor. Doctors call these states "off" periods. As you told me earlier, over the past week you typically spent ____ hours awake daily. Out of this waking time, how many total hours did your state of worsening, or "off" time, typically last ____?

(Use this number for your calculations).

0. Normal: No "off" periods.

1. Very mild: No more than 25% of waking time.

2. Mild: 26–50% of waking time.

3. Moderate: 51–75% of waking time.

4. Severe: More than 75% of waking time.

CALCULATION

1. Total duration of wakefulness
2. Total duration of "off" time
3. % "off" time = (2 / 1) × 100 _________________

4.4 FUNCTIONAL IMPACT OF FLUCTUATIONS

Investigator instructions: Determine the degree of impact of motor fluctuations on the patient's daily functions, including various daily activities and interactions with others. Scoring for this question is based on the differences between the "on" and "off" states. If no "off" periods occur, a score of 0 is given. A score of 0 is also given to patients with mild fluctuations if they do not affect the patient's functioning. To obtain the most accurate assessment, rely on the answers of the patient and caregiver to your questions, as well as your own observations during the patient's clinic visit.

Patient (and caregiver) instructions: Think back to the periods of worsening, or "off" periods, that you experienced over the past week. Did you notice more difficulty performing certain activities or interacting with others during these periods than during the rest of the day when your medications were working well? Are there activities that you usually manage during "good periods," but during "bad periods" you experience difficulty performing them or are forced to give them up?

0. Normal: No fluctuations, or they have no impact on the patient's functioning and interactions with others.

1. Very mild: Fluctuations affect specific activities, but during the "off" state the patient generally performs all activities and interactions with others available during "on" periods.

2. Mild: Fluctuations affect many activities, but during the "off" state the patient generally performs all activities and interactions with others available during "on" periods.

3. Moderate: Fluctuations affect the patient's activity to such an extent that they generally do not perform certain activities or certain interactions with others available during "on" periods.

4. Severe: The functional impact of fluctuations is so great that during the "off" state the patient generally does not perform most activities or most interactions with others available during "on" periods.

4.5 COMPLEXITY OF MOTOR FLUCTUATIONS

Instructions for the investigator: Determine the degree of predictability of "off" periods, their dependence on dose, time of day, food intake, or other factors. Use information obtained from the patient and caregivers, as well as your own observations. Ask the patient whether these episodes occur, in their opinion, at a specific time - always, most of the time (in this case, further clarification is needed to distinguish mild from very mild), only sometimes, or are they completely unpredictable? Evaluation in percentages will help you find the correct answer.

Patient (and caregiver) instructions: In some patients, periods of worsening or "off" periods occur at specific times during the day or are associated with a specific activity (e.g., eating or physical exertion). Over the past week, were you usually able to anticipate when your worsening periods would occur? In other words, did your worsening periods occur always at a specific time? Did they occur most of the time at a specific time? Did they occur only sometimes at a specific time? Or were the worsening periods completely unpredictable?

0. Normal: No motor fluctuations.

1. Very mild: "Off" periods are predictable always or almost always (more than 75% of the time).

2. Mild: "Off" periods are predictable most of the time (51–75%).

3. Moderate: "Off" periods are predictable some of the time (26–50%).

4. Severe: "Off" episodes are rarely predictable (no more than 25%).

C. "OFF"-PERIOD DYSTONIA

4.6 PAINFUL "OFF"-PERIOD DYSTONIA

Instructions for the examiner: For patients with motor fluctuations, determine what proportion of the "off" episode time is typically occupied by painful dystonia. You have already determined the duration of the "off" period (item 4.3). Estimate how many hours of the total "off" duration are associated with dystonia and calculate what percentage they represent. If "off" periods are absent, score 0.

Instructions for the patient (and caregiver): In response to one of the questions I asked earlier, you stated that overall, the "off" period—when your condition worsens because Parkinson's disease is poorly controlled—lasts ___ hours. During these worsening episodes, or "off" periods, how long do you typically experience painful spasms or muscle contractions? Out of the total duration of the "off" period (____ hours), how many hours do these painful spasms account for when summing up all episodes during the day?

0. Normal: No dystonia or "off" period.

1. Very mild: ≤ 25% of "off" time.

2. Mild: 26 - 50% of "off" time.

3. Moderate: 51 - 75% of "off" time.

4. Severe: More than 75% of "off" time.

CALCULATION

1. Total duration of "off" period (in hours) ___
2. Total duration of "off" period with dystonia (in hours) ____
3. % of "off" time with dystonia =(2/1)x100:_____________

Concluding remarks to the patient: READ TO THE PATIENT

This concludes my assessment of your condition. My questions and tasks took some time, but I wanted the evaluation to be as thorough as possible and to ensure all aspects were considered. That is why I asked about problems you have never had and perhaps never will have. Not all patients experience all of these problems, but since they can occur, it is important to ask every patient about them. Thank you for your time and attention during the assessment using this scale.

Template:

MDS-UPDRS Rating Scale Sheet

Notes: This scale is widely used as a screening method for diagnosing and assessing the severity of motor and non-motor symptoms, impairments in activities of daily living, and therapy complications.

Appendix G2. Mini-Mental State Examination

Original title: Mini Mental State Examination (MMSE)

Source: Folstein M.F., Folstein S.E., McHugh P.R. «Mini-mental state». A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 1975;12 (3): p. 189–198

Type: rating scale

Purpose: detection (screening) and assessment of the severity of cognitive impairment

Template:

Instructions for the Mini-Mental State Examination

1. Orientation in time. The maximum score (5) is given if the patient independently and correctly names the date, day of the week, month, year, and season. Each error or lack of response reduces the score by 1 point.

2. Place orientation. The question "Where are we?" is asked. If the patient's answer is incomplete, follow-up questions are asked. The patient must name the country, region, city, facility where the examination is taking place, and floor. Each error or lack of response reduces the score by 1 point.

3. Registration. The instruction is given: "Repeat and try to remember three words: apple, table, coin." The words should be pronounced as clearly as possible at a rate of one word per second. 1 point is awarded for each correctly repeated word. The words should be presented as many times as necessary for the subject to repeat them correctly, but only the first repetition is scored.

4. Attention and calculation. The patient is asked to serially subtract 7 from 100. Five subtractions are sufficient. Each error reduces the score by 1 point. If the patient is unable to perform this task, they are asked to spell the word "world" backwards. Each error reduces the score by 1 point.

5. Recall. The patient is asked to recall the words learned in item 3. Each correctly named word is worth 1 point.

6. Language.

A. A pen is shown and the patient is asked, "What is this?", similarly for a watch. Each correct answer is worth 1 point.

B. The patient is asked to repeat the grammatically complex phrase mentioned above. Correct repetition is scored 1 point.

C. A verbal command is given that involves the sequential performance of the three actions mentioned above. Each action is scored 1 point.

G. A written instruction is given (e.g., "Close your eyes"), and the patient is asked to read and perform it. The instruction must be written in sufficiently large printed letters on a clean sheet of paper.

E. The patient must independently write a meaningful and grammatically complete sentence.

F. The patient is given a model (two intersecting pentagons with equal angles / two crossed rectangles with equal angles), which they must copy on blank unlined paper. If spatial distortions or unjoined lines occur during copying, the command is considered incorrectly executed. Figure distortions caused by tremor are not taken into account.

The maximum total score on the scale is 30 points. 25–30 points: non-demented cognitive impairment or normal; 24 points or less: dementia (approximately 20–24 points: mild dementia; 11–19 points: moderate dementia; 0–10 points: severe dementia).

Notes: This scale is widely used as a screening method for assessing severe cognitive impairment, but it has its limitations. High frequency of use in the same patient is unacceptable due to potential practice effects (learning the questions). The scale has low sensitivity for diagnosing cognitive deficit in individuals with low and very high levels of education. It also lacks sufficient sensitivity in diagnosing pre-dementia cognitive impairment. It should be noted that the scale assesses the severity of cognitive disorders only approximately, particularly regarding the diagnosis of dementia, where confirmation of impaired functional status and activities of daily living is key for verification.

Appendix G3. Montreal Scale of Cognitive Assessment (MoCA)

Original title: The Montreal Cognitive Assessment (MoCA-test)

Source: www.mocatest.org

Type: rating scale

Purpose: detection (screening) and assessment of the severity of cognitive impairment

Template:

Full name: _______________________________________________________________________

Education: _________________________________________________________________

Date of birth: _______________________________________________________________

Date of examination: ____________________________________________________________

Visuospatial / Executive functions	Draw a clock showing ten minutes past eleven (3 points)	Score
		___/5
Naming		___/3
Attention Read a sequence of numbers (1 digit/s). Repeat forward 2 1 8 5 4. Repeat backward 7 4 2.		___/2
Read a sequence of letters. The patient must tap the table on every letter A. More than 2 errors = 0 pts. F B A V M N A A J L L B A F A K D E A A A J A M O F A A B		___/1
Serial 7s subtraction from 100 [ ] 93 [ ] 86 [ ] 79 [ ] 72 [ ] 65		___/ 3
Speech Repeat: I only know that John is on duty today. The cat always hid under the couch when the dog was in the room.		___/2
Speed Name as many words as possible starting with the letter "L" in one minute. (N≥11)		___/1
Abstraction Similarity between objects, e.g., banana and orange – fruit. train and bicycle                                          watch and ruler		___/2
Delayed recall Free recall Person Velvet Church Daisy Red Optional for completion Category cue Multiple choice cue		Score without cues ___/5
Orientation Date Day of the week Month Place Year City		___/6

Total score _____/30. Add 1 point if education ≤ 12 years.

Examination methodology and scoring

The Montreal Cognitive Assessment (MoCA) was developed as a rapid screening tool for mild cognitive impairment. It assesses various cognitive domains: attention and concentration, executive functions, memory, language, visuospatial skills, conceptual thinking, calculations, and orientation. The MoCA administration takes approximately 10 minutes. The maximum score is 30 points.

Normal score is 26 and above.

1. Trail Making Test:

Method: The subject is asked: "Draw a line from a number to a letter in ascending order. Start here (point to (1) and draw a line from 1 to A, then to 2, and so on. Finish here (point to (D).

Scoring: Allocate 1 point if the patient successfully draws the line in the following sequence: 1-A-2-B-3-C-4-D-5-E without any intersecting lines. Any error that is not immediately self-corrected earns 0 points.

2. Visuospatial skills (Cube):

Instructions: Point to the cube and give the following instructions: "Copy this drawing as accurately as possible in the space provided below."

Scoring: Award 1 point for a correctly copied figure:

• the drawing must be three-dimensional;

• all lines must be drawn;

• no extraneous lines should be added;

• lines must be relatively parallel and of comparable length (a drawing of a rectangular prism is acceptable).

The point is not awarded if any of the above-mentioned criteria are not met.

3. Visuospatial skills (Clock):

Instructions: Point to the right-hand third of the space and give the following instructions: "Draw a clock. Put in all the numbers and set the hands to show ten past eleven."

Scoring: Allocate 1 point for each of the following criteria met:

• contour (1 pt): the clock face must be a circle, with minor deformation acceptable (e.g., slight closure failure);

• numbers (1 pt): all numbers must be present with no extra numbers; numbers must be in the correct order and placed approximately in the correct quadrants of the clock face; Roman numerals are acceptable; numbers may be placed outside the circle contour;

• hands (1 pt): there must be two hands indicating the correct time; the hour hand must be clearly shorter than the minute hand; the hands must join inside the clock face contour and intersect close to the center.

The point is not awarded if any of the above-mentioned criteria are not met.

4. Naming:

Instructions: Pointing to the figures from left to right, ask: "Tell me the name of this animal."

Scoring: Award 1 point for each correct response: (1) lion, (2) rhinoceros, (3) camel.

5. Memory:

Instructions: Read a list of 5 words at a rate of one per second, giving the following instructions: "This is a memory test. I am going to read a list of words that you will have to remember now and recall later. Listen carefully. When I am through, tell me as many words as you can remember. It doesn't matter in what order you say them." Mark a check in the designated space for each word the patient produces on the first trial. When the patient indicates they have finished (or cannot recall any more words), read the list a second time with the following instructions: "I am going to read the same list for a second time. Try to remember and tell me as many words as you can, including the ones you said the first time." Put a check in the corresponding space for each word the patient recalls on the second trial.

At the end of the second trial, inform the patient: "I will ask you to recall those same words again at the end of the test."

Scoring: No points are awarded for trials 1 and 2.

6. Attention:

Forward Digit Span:

Instructions: Give the following instructions: "I am going to say some numbers and after I am finished, you must repeat them back to me exactly as I said them." Read a sequence of five numbers at a rate of one per second.

Backward Digit Span:

Instructions: Give the following instructions: "Now I am going to say some more numbers, but when I am finished, you must repeat them back to me in reverse order." Read a sequence of three numbers at a rate of one per second.

Scoring: Allocate 1 point for each correctly repeated sequence (N.B.: the correct backward response is 2-4-7).

Vigilance

Instructions: Read a sequence of letters at a rate of one per second, giving the following instructions: "I am going to read a sequence of letters. Every time I say the letter A, tap your hand once. If I say any other letter, do not tap your hand."

Scoring: Award 1 point if there is zero or one error (an error is a tap on a wrong letter or a failure to tap on letter A).

Serial 7s subtraction test:

Instructions: Give the following instructions: "Now I will ask you to count backward by subtracting 7 from 100, and then keep subtracting 7 from your answer until I tell you to stop." Repeat instructions if necessary.

Scoring: This item is evaluated out of 3 points. 0 points for no correct subtractions, 1 point for one correct subtraction, 2 points for 2 to 3 correct subtractions, and 3 points for 4 to 5 correct subtractions. Count all correct 7s subtractions starting from 100. Each subtraction is evaluated independently; therefore, if the patient makes a mistake but continues to correctly subtract 7 from the previous incorrect result, credit is given for each correct calculation step.

For example, a patient may respond: "92-85-78-71-64" — even though 92 is an incorrect starting result, all subsequent subtractions are performed correctly. This response receives 3 points.

7. Sentence repetition:

Instructions: Give the following instructions: "I am going to read you a sentence. Repeat it after me, exactly as I say it (pause): I only know that John is the one to help today." Following the response, say: "Now I am going to read you another sentence. Repeat it after me, exactly as I say it (pause): The cat always hid under the couch when dogs were in the room."

Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. Watch for errors such as substituting words (e.g., omissions, additions, word changes like "that" instead of "which", changes in singular/plural, etc.).

8. Verbal fluency:

Instructions: Give the following instructions: "Tell me as many words as you can think of that begin with a particular letter of the alphabet that I will tell you in a moment. You can say any kind of word you want, except for proper nouns (e.g., Mary, Moscow), numbers, or grammatical variations of the same word (e.g., house, housing, housed). I will stop you after one minute. Are you ready? (Pause) Now, tell me as many words as you can think of that begin with the letter F. (60 seconds) Stop."

Scoring: Allocate 1 point if the patient generates 11 words or more in 60 seconds. Record the patient's result.

9. Abstraction:

Instructions: Ask the patient to explain what each pair of items has in common, starting with the example: "Tell me how an orange and a banana are alike." If the patient answers in concrete terms, prompt them once: "Tell me another way they are alike." If the patient does not express the category "fruit", say: "Yes, and they are both fruits." Do not give any additional explanations or hints.

After the practice trial, say: "Now, tell me how a train and a bicycle are alike." Following the response, administer the second trial: "Now, tell me how a ruler and a watch are alike." Do not give any additional instructions or prompts.

Scoring: Only the two test pairs are scored. Allocate 1 point for each correct response. The following answers are acceptable:

Train - bicycle = means of transportation, travel, vehicles, you can ride them;

Ruler - watch = measuring instruments, used for measurement.

Unacceptable answers: Train - bicycle = they have wheels; ruler - watch = they both have numbers.

10. Delayed recall:

Method: Give the following instructions: "I read some words to you and asked you to memorize them. Name those words from the list that you remember." Check the boxes corresponding to the words that were recalled independently without prompting.

Scoring: Allocate 1 point for each word recalled freely without cues.

Optional:

Following free recall, provide a category cue for all words not recalled spontaneously. Put a check mark in the corresponding category column if the patient remembers the word with a semantic cue or multiple-choice recognition. Provide category cues for all words not recalled. If the patient still fails to recall the word after a category cue, give them a multiple-choice recognition task, e.g., "Which of the following words do you think it was: NOSE, FACE, or HAND?"

Scoring: Words recalled with a cue are not scored with points. Cues are used for clinical assessment only. They provide additional information on the type of memory impairment. In recall impairments, performance can be improved by a cue. In encoding impairments, performance is not improved by a cue.

11. Orientation:

Procedure: Give the following instructions: "State today's date." If the subject does not give a full answer, prompt them: "Tell me the year/month/date/day of the week." Then ask: "State the name of the place where we are, and of this city."

Scoring: One point is awarded for each correct answer. The subject must state the exact date and location (name of the clinic, hospital, outpatient clinic). An answer with an error of one day in the date or day of the week is not credited.

Total score: One point is added to the total score if the subject has 12 years of education or less. The maximum score is 30. A normal score is 26 and above.

Notes: This scale is widely used as a screening method for diagnosing severe cognitive impairment. The scale has sensitivity in diagnosing predemented cognitive impairment.

Appendix G4. Hospital Anxiety and Depression Scale (HADS)

Original title: Hospital Anxiety and Depression Scale (HADS)

Source: Prisnie JC, Fiest KM, Coutts SB, Patten SB, Atta CA, Blaikie L, et al. Validating screening tools for depression in stroke and transient ischemic attack patients. Int J Psychiatry Med. (2016) 51:262–77.

Type: rating scale

Purpose: primary identification (screening) of depression and anxiety in general medical practice

Template:

Full name ____________________________________

Date: ____________________________________

Part I

1. I feel tense or 'wound up'.

3 - most of the time

2 - a lot of the time

1 - from time to time, occasionally

0 - not at all

2. I get a sort of frightened feeling as if something awful is about to happen.

3 - very definitely and quite severely

2 - yes, but not too badly

1 - a little, but it doesn't worry me

0 - not at all

3. Worrying thoughts go through my mind.

3 - a great deal of the time

2 - a lot of the time

1 - from time to time, but not too often

0 - only occasionally

4. I can sit at ease and feel relaxed.

0 - definitely

1 - usually

2 - not often

3 - not at all

5. I get a sort of frightened feeling like 'butterflies' in the stomach.

0 - not at all

1 - occasionally

2 - a lot of the time

3 - very often

6. I feel restless as I have to be on the move.

3 - very much indeed

2 - quite a lot

1 - not very much

0 - not at all

7. I get sudden feelings of panic.

3 - very often

2 - quite a lot

1 - not very often

0 - not at all

Part II

1. I still enjoy the things I used to enjoy.

0 - definitely

1 - probably as much

2 - only a very little

3 — not at all

2. I can laugh and see the funny side of things.

0 - definitely

1 - probably as much

2 - only a very little

3 — not at all

3. I feel cheerful.

3 — not at all

2 — very rarely

1 - occasionally

0 — almost all the time

4. I feel as if I am slowed down a lot.

3 — almost all the time

2 - a lot of the time

1 - occasionally

0 — not at all

5. I have lost all interest in my appearance.

3 - very much indeed

2 — I do not take as much care of it as I should

1 — I may take a little less care than I used to

0 — I take just as much care as ever

6. I look forward with enjoyment to things.

0 — as much as I ever did

1 — rather less than I used to

2 — definitely less than I used to

3 — hardly at all

7. I can get a good laugh and see the funny side of things.

0 — as much as I ever could

1 - occasionally

2 — rather less than I used to

3 — definitely not so much now

Instructions. Each item on the HADS scale corresponds to 4 possible answers. The patient is asked to choose the answer that best describes how they have felt over the past 7 days, and the scores are then summed separately for each subscale.

Interpretation:

- 0–7 points — normal: no significant symptoms of anxiety/depression.

- 8–10 points — borderline (subclinical) anxiety/depression.

- 11 points and above — clinical anxiety/depression.

Examples:

- Example 1. The anxiety score (left) is 11, and the depression score (right) is 3. This indicates the presence of clinical anxiety, while the depression level is within the normal range.

- Example 2. The anxiety score is 15, and the depression score is 9. This indicates the presence of clinical anxiety and subclinical depression.

- Example 3. The anxiety score is 6, and the depression score is 1. This indicates that both anxiety and depression levels are within the normal range.

Patient Instructions:

Each statement has 4 possible answers. Please choose the answer that best corresponds to your current condition.

Notes: This scale is widely used as a screening tool for depression and anxiety in general practice.